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CYP3A4 DDI Qualification

Version 2.2-OSP12.3
Qualification Plan Release https://github.com/Open-Systems-Pharmacology/Qualification-DDI-CYP3A4/releases/tag/v2.2
OSP Version 12.3
Qualification Framework Version 3.6

This qualification report is filed at:

https://github.com/Open-Systems-Pharmacology/OSP-Qualification-Reports

Table of Contents

1 Introduction

1.1 Objective

This qualification report evaluates for the PBPK platform PK-Sim (as part of the open systems pharmacology (OSP) suite) the ability to perform simulations with the intended purpose to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDI).

To demonstrate the level of confidence, the predictive performance of the platform for this indented purpose is assessed via a network of PBPK models of selected index CYP3A4 DDI perpetrators (covering the range from strong induction to strong inhibition), and respective sensitive index CYP3A4 victim drugs and a comprehensive dataset from published clinical DDI studies. All PBPK models represent whole-body PBPK models, which allow dynamic DDI simulations in organs expressing CYP3A4.

The respective qualification plan to produce this qualification report is transparently provided open-source (https://github.com/Open-Systems-Pharmacology/Qualification-DDI-CYP3A4). The same applies for all presented PBPK models including evaluation reports on model building and evaluation of each model (https://github.com/Open-Systems-Pharmacology/OSP-PBPK-Model-Library).

Evaluation reports including descriptions on model building and detailed evaluations of the included models are documented separately (see Section 1.2).

Please refer to the Appendix to learn more details:

  • An overview over the Open Systems Pharmacology Suite is given in chapter Section 5.1

  • Section 5.2 shows the implementation of the underlying mathematical equations for drug-drug interactions in the OSP suite.

  • A detailed general description of the performed qualification workflow (qualification plan, qualification report, etc.) can be found in chapter Section 5.3.

1.2 CYP3A4 DDI Network

To qualify the OSP suite for the prediction of the CYP3A4 DDI potential of new drugs, a set of verified PBPK models of index perpetrators, covering the range from strong CYP3A4 induction to strong inhibition, and respective CYP3A4 DDI victim drugs is specified to set up a CYP3A4-mediated DDI modeling network.

The following perpetrator compounds were selected:

The following sensitive CYP3A4 substrates as victim drugs were selected:

Figure 1 shows the prespecified and developed DDI modeling network of interacting perpetrator and victim drugs for the OSP suite qualification of predicting CYP3A4-mediated DDI.

Figure 1: CYP3A4 DDI modeling network

DDI CYP3A4 network

The arrows indicate where at least one clinical DDI study between the two connected substances was available and included in the model network. Red indicates inhibition and green indicates induction as the primary type of interaction. Thin arrows indicate weak, mid-thick arrows moderate and thick arrows strong CYP3A4 modulation by the perpetrator.

The published DDI studies between the respective perpetrators and victim drugs were simulated and compared to observed data. The following sections give an overview of the clinical studies being part of this qualification report. The respective data identifier (DataID) refers to the ID of the dataset in the OSP PK database, version 1.9 (https://github.com/Open-Systems-Pharmacology/Database-for-observed-data/releases/tag/v1.9).

1.2.1 Carbamazepine - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Carbamazepine-Alprazolam-DDI/releases/tag/v1.1

The carbamazepine-alprazolam interaction was evaluated using one clinical DDI study (Furukori 1998).

DataID Enzyme Perpetrator / victim Study design Clinical study
1457 CYP3A4 Carbamazepine / alprazolam Carbamazepine: 100 mg po TID for 10 days
Alprazolam: 0.8 mg po single dose, 2 hours after the 22nd carbamazepine dose		 Furukori 1998

1.2.2 Carbamazepine - Efavirenz DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Carbamazepine-Efavirenz-DDI/releases/tag/v1.1

The carbamazepine-efavirenz interaction was evaluated using one clinical DDI study (Ji 2008).

DataID Enzyme Perpetrator / victim Study design Clinical study
959 CYP3A4 Carbamazepine / efavirenz Study Arm 1:
Carbamazepine (starting with the 15th dose of efavirenz): 200 mg po QD for 3 days, followed by 200 mg po BID for 3 days, followed by 400 mg po QD for 16 days
Efavirenz: 600 mg po QD for 35 days		 Ji 2008

1.2.3 Carbamazepine - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Carbamazepine-Midazolam-DDI/releases/tag/v1.1

The carbamazepine-midazolam interaction was evaluated using three clinical DDI studies (Lutz 2018, Kanefendt 2023, Datta-Mannan 2024).

DataID Enzyme Perpetrator / victim Study design Clinical study
1460 CYP3A4 Carbamazepine / midazolam Carbamazepine: 100 mg po BID for 2 days, followed by 200 mg po BID for 2 days, followed by 300 mg po BID for 22 days
Midazolam: 2 mg po single dose, concomitantly with the 49th carbamazepine dose		 Lutz 2018
943 CYP3A4 Carbamazepine / midazolam Carbamazepine: 100 mg po BID for 2 days, followed by 200 mg po BID for 2 days, followed by 300 mg po BID for 17 days
Midazolam: 1 mg po single dose, 10 hours after the 26th carbamazepine dose		 Kanefendt 2023
1133 CYP3A4 Carbamazepine / midazolam Carbamazepine: 100 mg po BID for 2 days, followed by 200 mg po BID for 2 days, followed by 300 mg po BID for 18 days
Midazolam: 1 mg po single dose, 12 hours after the 28th carbamazepine dose		 Kanefendt 2023
1464 CYP3A4 Carbamazepine / midazolam Carbamazepine: 100 mg po BID for 3 days, followed by 200 mg po BID for 3 days, followed by 300 mg po BID for 4 days
Midazolam: 1 mg po single dose, concomitantly with the 19th carbamazepine dose		 Datta-Mannan 2024
1465 CYP3A4 Carbamazepine / midazolam Carbamazepine: 100 mg po BID for 3 days, followed by 200 mg po BID for 3 days, followed by 300 mg po BID for 7 days
Midazolam: 1 mg po single dose, concomitantly with the 25th carbamazepine dose		 Datta-Mannan 2024

1.2.4 Cimetidine - Alfentanil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Alfentanil-DDI/releases/tag/v1.2.

The cimetidine-alfentanil interaction was evaluated using a single clinical DDI study quantifying the interaction following two different dosing regimens (Kienlen 1993).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1344 CYP3A4 Cimetidine / alfentanil Cimetidine: 1200 mg iv OD over 3 days
Alfentanil: 125 µg/kg iv on day 3 concomitantly with the cimetidine dose		 No cross-over study! Parallel group design -> the two groups may not really be comparable given the low number of subjects and considering alfentanil PK variability Kienlen 1993

1.2.5 Cimetidine - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Alprazolam-DDI/releases/tag/v1.2

The cimetidine-alprazolam interaction was evaluated using two clinical DDI studies quantifying the interaction following two different dosing regimens (Pourbaix 1985, Abernethy 1983).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1340 CYP3A4 Cimetidine / alprazolam Cimetidine: 200 mg po TID and 400 mg at bedtime over two weeks
Alprazolam: 0.5 mg po OD in the second week concomitantly with morning dose		 Pourbaix 1985
1332 CYP3A4 Cimetidine / alprazolam Cimetidine: 300 mg po QID (4 times)
Alprazolam: 1 mg po single dose concomitantly with cimetidine dose at 12 h		 Abernethy 1983

1.2.6 Cimetidine - Carbamazepine DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Carbamazepine-DDI/releases/tag/v1.2

The cimetidine-carbamazepine interaction was evaluated using one clinical DDI study (Dalton 1985).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
900 CYP3A4 Cimetidine / carbamazepine Cimetidine: 300 mg po QID for 9 days
Carbamazepine: 600 mg po single dose, one hour before the 9th dose of cimetidine		 Dalton 1985

1.2.7 Cimetidine - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Midazolam-DDI/releases/tag/v1.2

The cimetidine-midazolam interaction was evaluated using five clinical DDI studies quantifying the interaction following six different dosing regimens (Elliott 1984, Fee 1987, Greenblatt 1986, Martinez 1999, Salonen 1986).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1346 CYP3A4 Cimetidine / midazolam Cimetidine: 200 mg po TID and 400 mg nocte on day before study and 200 mg on study day
Midazolam: 7.5 mg po single dose, 2.5 hours after last cimetidine dose		 Elliott 1984
1324 CYP3A4 Cimetidine / midazolam Cimetidine: 400 mg po BID (3 times)
Midazolam: 15 mg po single dose, 1 hour after the last cimetidine dose		 Fee 1987
1319 CYP3A4 Cimetidine / midazolam Cimetidine: 300 mg po QID (8 times)
Midazolam: 5 mg iv single dose, concomitantly with the 5th cimetidine dose		 Greenblatt 1986
1321 CYP3A4 Cimetidine / midazolam Cimetidine: 300 mg po QID (8 times)
Midazolam: 15 mg po single dose concomitantly with the 5th cimetidine dose		 Greenblatt 1986
1322 CYP3A4 Cimetidine / midazolam Cimetidine: 800 mg po single dose
Midazolam: 7.5 mg po single dose concomitantly with cimetidine dose		 Martinez 1999
1326 CYP3A4 Cimetidine / midazolam Cimetidine: 400 mg po single dose
Midazolam: 15 mg po single dose 2 hours after cimetidine dose		 Salonen 1986

1.2.8 Cimetidine - Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Triazolam-DDI/releases/tag/v1.2

The cimetidine-triazolam interaction was evaluated using four clinical DDI studies quantifying the interaction following four different dosing regimens (Pourbaix 1985, Abernethy 1983, Cox 1986, Friedman 1988).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1342 CYP3A4 Cimetidine / triazolam Cimetidine: 200 mg po TID and 400 mg at bedtime over two weeks
Triazolam: 0.5 mg po OD in the second week concomitantly with bedtime dose		 Pourbaix 1985
1334 CYP3A4 Cimetidine / triazolam Cimetidine: 300 mg po QID (4 times)
Triazolam: 0.5 mg po single dose concomitantly with cimetidine dose at 12 h		 Abernethy 1983
1338 CYP3A4 Cimetidine / triazolam Cimetidine: 300 mg po QID (4 times)
Triazolam: 0.5 mg intraduodenal single dose, 13 hours after study start		 Cox 1986
1336 CYP3A4 Cimetidine / triazolam Cimetidine: 300 mg po QID (8 times)
Triazolam: 0.5 mg po single dose concomitantly with the 5th cimetidine dose		 Friedman 1988

1.2.9 Cimetidine - Verapamil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Cimetidine-Verapamil-DDI/releases/tag/v2.0

The cimetidine-verapamil interaction was evaluated using four clinical DDI studies quantifying the interaction following seven different dosing regimens (Abernethy 1985, Mikus 1990, Smith 1984, Wing 1985).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
16149 CYP3A4 Cimetidine / verapamil Cimetidine: 300 mg po QID over two days (7 administrations)
Verapamil: 10 mg iv 12h after first cimetidine dosing		 Abernethy 1985
16150 CYP3A4 Cimetidine / verapamil Cimetidine: 300 mg po QID over two days (7 administrations)
Verapamil: 120 mg po 12h after first cimetidine dosing		 Abernethy 1985
16151 - 16154 CYP3A4 Cimetidine / verapamil Cimetidine: 400 mg po BID over seven days
Verapamil: 160 mg po on day 7 30 minutes after the morning dose		 Mikus 1990
1328 CYP3A4 Cimetidine / verapamil Cimetidine: 300 mg po QID over eight days
Verapamil: 10 mg iv on day 8 concomitantly with the morning dose		 Smith 1984
1330 CYP3A4 Cimetidine / verapamil Cimetidine: 300 mg po QID over eight days
Verapamil: 120 mg po on day 8 concomitantly with the morning dose		 Smith 1984
16155 CYP3A4 Cimetidine / verapamil Cimetidine: 200 mg po three times daily and 400mg at night over nine days
Verapamil: 10 mg iv on day 8		 Wing 1985
16156 CYP3A4 Cimetidine / verapamil Cimetidine: 200 mg po three times daily and 400mg at night over nine days
Verapamil: 80 mg po on day 8		 Wing 1985

1.2.10 Clarithromycin - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Clarithromycin-Midazolam-DDI/releases/tag/v1.2

The clarithromycin-midazolam interaction was evaluated using eight clinical DDI studies quantifying the interaction following ten different dosing regimens (Gorski 1998, Gurley 2006, Gurley 2008a, Markert 2013, Prueksaritanont 2017, Quinney 2008, van Dyk 2018, Yeates 1997).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
175 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 0.05 mg/kg iv single dose, 2 hours after the 13th clarithromycin dose		 Gorski 1998
173 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 4 mg po single dose, 2 hours after the 13th clarithromycin dose		 Gorski 1998
217 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 8 mg po single dose, 2 hours after the 13th clarithromycin dose		 Gurley 2006
223 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 8 mg po single dose, 2 hours after the 13th clarithromycin dose		 Gurley 2008a
354 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 4 days
Midazolam: 3 mg po single dose, 0.25 hours after the 7th clarithromycin dose		 Markert 2013
1099 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 5 days
Midazolam: 0.01 mg po single dose, administered simultaneously with the 7th clarithromycin dose		 Prueksaritanont 2017
2027 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 0.05 mg/kg iv single dose, 2 hours after the 13th clarithromycin dose		 Quinney 2008
2030 CYP3A4 Clarithromycin / midazolam Clarithromycin: 500 mg po BID for 7 days
Midazolam: 3.5 mg po single dose, 2 hours after the 13th clarithromycin dose		 Quinney 2008
2004 CYP3A4 Clarithromycin / midazolam Rifampicin: 300 mg po QD for 7 days
Wash-out phase for 3 days
Clarithromycin: 250 mg po BID for 3 days
Midazolam: 1 mg po single dose, 12 hours after the last rifampicin dose and again 12 hours after the last clarithromycin dose		 Only assessment in Caucasian subjects simulated.
AUC0-6h ratio reported and simulated for comparison.		 van Dyk 2018
469 CYP3A4 Clarithromycin / midazolam Clarithromycin: 250 mg po BID for 5 days
Midazolam: 15 mg po single dose, 1.5 hours after the 9th clarithromycin dose		 Yeates 1997

1.2.11 Clarithromycin - Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Clarithromycin-Triazolam-DDI/releases/tag/v1.2

The clarithromycin-triazolam interaction was evaluated using one clinical DDI study (Greenblatt 1998a).

DataID Enzyme Perpetrator / victim Study design Clinical study
1102 CYP3A4 Clarithromycin / triazolam Clarithromycin: 500 mg po twice daily at irregular time intervals for 2 days
Triazolam: 0.125 mg po single dose, 1 hour after the 3rd clarithromycin dose		 Greenblatt 1998a

1.2.12 Efavirenz - Alfentanil-DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Efavirenz-Alfentanil-DDI/releases/tag/v1.1

The efavirenz-alfentanil interaction was evaluated using one clinical DDI study that includes iv and oral administration of alfentanil (Kharasch 2012).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
801 CYP3A4 Efavirenz / alfentanil Efavirenz: 600 mg po OD for 20 days
Alfentanil: 43 µg/kg po single dose, 1/2 hour after the 15th efavirenz dose		 Kharasch 2012
803 CYP3A4 Efavirenz / alfentanil Efavirenz: 600 mg po OD for 20 days
Alfentanil: 15 µg/kg iv single dose, 1/2 hour after the 16th efavirenz dose		 Kharasch 2012

1.2.13 Efavirenz - Carbamazepine DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Efavirenz-Carbamazepine-DDI/releases/tag/v1.0

The efavirenz-carbamazepine interaction was evaluated using one clinical DDI study (Ji 2008).

DataID Enzyme Perpetrator / victim Study design Clinical study
961 CYP3A4 Efavirenz / carbamazepine Study Arm 2:
Efavirenz (starting with the 25th dose of carbamazepine): 600 mg po QD for 14 days
Carbamazepine: 200 mg po QD for 3 days, followed by 200 mg po BID for 3 days, followed by 400 mg po QD for 30 days		 Ji 2008

1.2.14 Efavirenz - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Efavirenz-Midazolam-DDI/releases/tag/v1.2

The efavirenz-midazolam interaction was evaluated using two clinical DDI studies, one using single dose and one using one multiple dose administration of efavirenz (Katzenmaier 2010, Mikus 2017).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
2041 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po OD over 14 days
Midazolam: 3 mg po single dose on day 14 together with efavirenz dose		 Katzenmaier 2010
2044 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 4 mg po single dose, 12 hours (day 1) after efavirenz dose		 Mikus 2017
2045 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 2 mg iv single dose, 18 hours (day 1) after efavirenz dose		 Mikus 2017
2047 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 4 mg po single dose, 132 hours (day 6) after efavirenz dose		 Mikus 2017
2048 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 2 mg iv single dose, 138 hours (day 6) after efavirenz dose		 Mikus 2017
2049 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 4 mg po single dose, 252 hours (day 11) after efavirenz dose		 Mikus 2017
2050 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 2 mg iv single dose, 258 hours (day 11) after efavirenz dose		 Mikus 2017
2051 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 4 mg po single dose, 372 hours (day 16) after efavirenz dose		 Mikus 2017
2052 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 2 mg iv single dose, 378 hours (day 16) after efavirenz dose		 Mikus 2017
2053 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 4 mg po single dose, 516 hours (*day 22) after efavirenz dose		 Mikus 2017
2054 CYP3A4 Efavirenz / midazolam Efavirenz: 400 mg po SD on day 1
Midazolam: 2 mg iv single dose, 522 hours (day 22) after efavirenz dose		 Mikus 2017

1.2.15 Erythromycin - Alfentanil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Erythromycin-Alfentanil-DDI/releases/tag/v1.2

The erythromycin-alfentanil interaction was evaluated using one clinical DDI study (Bartkowski 1989) quantifying the interaction following two different dosing regimens. Additionally, the plasma concentration-time profile of an individual investigated in this study was subsequently reported in a later study (Bartkowski 1993).

DataID Enzyme Perpetrator / victim Study design Clinical study
779 CYP3A4 Erythromycin / alfentanil Erythromycin: 500 mg po single dose (enteric coated tablet containing erythromycin as free base)
Alfentanil: 0.05 mg/kg iv single dose, 1.5 hours after erythromycin dose		 Bartkowski 1989
780 CYP3A4 Erythromycin / alfentanil Erythromycin: 500 mg po BID for 7 days (enteric coated tablet containing erythromycin as free base)
Alfentanil: 0.05 mg/kg iv single dose, 1.5 hours after the 13th erythromycin dose		 Bartkowski 1989

1.2.16 Erythromycin - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Erythromycin-Alprazolam-DDI/releases/tag/v1.3

The erythromycin-alprazolam interaction was evaluated using one clinical DDI study (Yasui 1996).

DataID Enzyme Perpetrator / victim Study design Clinical study
777 CYP3A4 Erythromycin / alprazolam Erythromycin: 400 mg po TID for 10 days (filmcoated tablet containing erythromycin stearate)
Alprazolam: 0.8 mg po single dose, 2 hours after the 22nd erythromycin dose		 Yasui 1996

1.2.17 Erythromycin - Carbamazepine DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Erythromycin-Carbamazepine-DDI/releases/tag/v1.2

The erythromycin-carbamazepine interaction was evaluated using three clinical DDI studies (Barzaghi 1987, Miles 1989, Wong 1983).

DataID Enzyme Perpetrator / victim Study design Clinical study
465 CYP3A4 Erythromycin / carbamazepine Erythromycin: 500 mg po TID for 10 days
Carbamazepine: 400 mg po single dose, administered on the 7th day of treatment with erythromycin		 Barzaghi 1987
1157 CYP3A4 Erythromycin / carbamazepine Erythromycin: 250 mg po QID for 3 days, starting on day 15 of carbamazepine administration
Carbamazepine: 300 mg po QD for 17 days		 Miles 1989
1158 CYP3A4 Erythromycin / carbamazepine Erythromycin: 250 mg po QID for 3 days, starting on day 15 of carbamazepine administration
Carbamazepine: 400 mg po QD for 17 days		 Miles 1989
1154 CYP3A4 Erythromycin / carbamazepine Erythromycin: 250 mg po QID for 8 days
Carbamazepine: 400 mg po single dose, administered on the 6th day of treatment with erythromycin		 Wong 1983

1.2.18 Erythromycin - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Erythromycin-Midazolam-DDI/releases/tag/v1.2

The erythromycin-midazolam interaction was evaluated using five clinical DDI studies quantifying the interaction following nine different dosing regimens (Carls 2014, Okudaira 2007, Olkkola 1993, Swart 2002, Zimmermann 1996).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
828 CYP3A4 Erythromycin / midazolam Erythromycin: 250 mg po single dose (filmcoated tablet containing erythromycin stearate)
Midazolam: 0.03 mg po single dose, 1 hour after erythromycin dose		 AUC2-4h ratio reported and simulated for comparison. Carls 2014
829 CYP3A4 Erythromycin / midazolam Erythromycin: 1000 mg single dose (filmcoated tablet containing erythromycin stearate)
Midazolam: 0.03 mg po single dose, 1 hour after erythromycin dose		 AUC2-4h ratio reported and simulated for comparison. Carls 2014
362 CYP3A4 Erythromycin / midazolam Erythromycin: 200 mg po four times daily for 7 days (filmcoated tablet containing erythromycin stearate)
Midazolam: 2.5 mg po single dose, 1 hour after the 5th erythromycin dose		 Subjects received 5 mg midazolam po in control phase Okudaira 2007
363 CYP3A4 Erythromycin / midazolam Erythromycin: 200 mg po four times daily for 7 days (filmcoated tablet containing erythromycin stearate)
Midazolam: 2.5 mg po single dose, 1 hour after the 13th erythromycin dose		 Subjects received 5 mg midazolam po in control phase Okudaira 2007
364 CYP3A4 Erythromycin / midazolam Erythromycin: 200 mg po four times daily for 7 days (filmcoated tablet containing erythromycin stearate)
Midazolam: 2.5 mg po single dose, 1 hour after the 25th erythromycin dose		 Subjects received 5 mg midazolam po in control phase Okudaira 2007
368 CYP3A4 Erythromycin / midazolam Erythromycin: 500 mg po TID for 6 days (enteric coated tablet containing erythromycin as free base)
Midazolam: 0.05 mg/kg iv single dose, 2 hours after the 17th erythromycin dose		 Olkkola 1993
366 CYP3A4 Erythromycin / midazolam Erythromycin: 500 mg po TID for 6 days (enteric coated tablet containing erythromycin as free base)
Midazolam: 15 mg po single dose, 2 hours after the 17th erythromycin dose		 Olkkola 1993
420 CYP3A4 Erythromycin / midazolam Erythromycin: 500 mg po QID for 5 days (filmcoated tablet containing erythromycin stearate)
Midazolam: 0.075 mg/kg mg iv single dose, together with the 96th erythromycin dose		 Swart 2002
471 CYP3A4 Erythromycin / midazolam Erythromycin: 500 mg po TID for 5 days (filmcoated tablet containing erythromycin stearate)
Midazolam: 0.8 mg po single dose, 1.5 hours after the 13th erythromycin dose		 Zimmermann 1996

1.2.19 Erythromycin - Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Erythromycin-Triazolam-DDI/releases/tag/v1.2

The erythromycin-triazolam interaction was evaluated using two clinical DDI studies (Greenblatt 1998, Phillips 1986).

DataID Enzyme Perpetrator / victim Study design Clinical study
781 CYP3A4 Erythromycin / triazolam Erythromycin: 500 mg po twice daily for 2 days
Triazolam: 0.125 mg po single dose, 1 hour after the 3rd erythromycin dose		 Greenblatt 1998
757 CYP3A4 Erythromycin / triazolam Erythromycin: 333 mg po TID for 3 days
Triazolam: 0.5 mg po single dose, together with the last erythromycin dose		 Phillips 1986

1.2.20 Fluconazole - Alfentanil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Fluconazole-Alfentanil-DDI/releases/tag/v1.0

The fluconazole-alfentanil interaction was evaluated using a single clinical DDI study quantifying the interaction following two different dosing regimens (Palkama 1998).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1398 CYP3A4 Fluconazole / alfentanil Fluconazole: 400 mg iv infusion for 60 min single administration
Alfentanil: 0.02 mg/kg iv infusion, 1 hour after start of fluconazole dosing		 Palkama 1998
1399 CYP3A4 Fluconazole / alfentanil Fluconazole: 400 mg po single administration
Alfentanil: 0.02 mg/kg iv infusion, 1 hour after the fluconazole dose		 Palkama 1998

1.2.21 Fluconazole - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Fluconazole-Midazolam-DDI/releases/tag/v1.0

The fluconazole-midazolam interaction was evaluated using two clinical DDI studies quantifying the interaction following 5 different dosing regimens (Ahonen 1997, Olkkola 1996).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1392 CYP3A4 Fluconazole / midazolam Fluconazole: 400 mg iv infusion for 60 min
Midazolam: 7.5 mg po single dose, 1 hour after start of fluconazole dosing		 Ahonen 1997
1393 CYP3A4 Fluconazole / midazolam Fluconazole: 400 mg po
Midazolam: 7.5 mg po single dose, 1 hour after the fluconazole dose		 Ahonen 1997
380 CYP3A4 Fluconazole / midazolam Fluconazole: 400 mg po QD (day 1) then 200 mg QD for 5 days
Midazolam: 7.5 mg po, 2 hours after the day 1 fluconazole dose		 Olkkola 1996
381 CYP3A4 Fluconazole / midazolam Fluconazole: 400 mg po QD (day 1) then 200 mg QD for 5 days
Midazolam: 0.05 mg/kg iv infusion, 2 hours after the day 4 fluconazole dose		 Olkkola 1996
381 CYP3A4 Fluconazole / midazolam Fluconazole: 400 mg po QD (day 1) then 200 mg QD for 5 days
Midazolam: 7.5 mg po, 2 hours after the day 6 fluconazole dose		 Olkkola 1996

1.2.22 Fluconazole - Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Fluconazole-Triazolam-DDI/releases/tag/v1.0

The fluconazole-triazolam interaction was evaluated using a single clinical DDI study quantifying the interaction following three different dosing regimens (Varhe 1996).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1394 CYP3A4 Fluconazole / triazolam Fluconazole: 50 mg po QD for 4 days
Triazolam: 0.25 mg po single dose, 1 hour after last fluconazole dose		 Varhe 1996
1395 CYP3A4 Fluconazole / triazolam Fluconazole: 100 mg po QD for 4 days
Triazolam: 0.25 mg po single dose, 1 hour after last fluconazole dose		 Varhe 1996
1396 CYP3A4 Fluconazole / triazolam Fluconazole: 200 mg po QD for 4 days
Triazolam: 0.25 mg po single dose, 1 hour after last fluconazole dose		 Varhe 1996

1.2.23 Fluvoxamine - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Fluvoxamine-Alprazolam-DDI/releases/tag/v1.1

The fluvoxamine-alprazolam interaction was evaluated using one clinical DDI study quantifying the interaction following the first dose and in steady-state (Fleishaker 1994).

DataID Enzyme Perpetrator / victim Study design Clinical study
1104 CYP3A4 Fluvoxamine / alprazolam Fluvoxamine: 50 mg fluvoxamine maleate QD for 3 days, followed by 100 mg fluvoxamine maleate QD for 7 days
Alprazolam: 1 mg po four times daily on Day 7 starting together with the 7th fluvoxamine dose		 Fleishaker 1994
1113 CYP3A4 Fluvoxamine / alprazolam Fluvoxamine: 50 mg fluvoxamine maleate QD for 3 days, followed by 100 mg fluvoxamine maleate QD for 7 days
Alprazolam: 1 mg po four times daily on Days 7 - 10 starting together with the 7th fluvoxamine dose		 Fleishaker 1994

1.2.24 Fluvoxamine - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Fluvoxamine-Midazolam-DDI/releases/tag/v1.2

The fluvoxamine / midazolam interaction was evaluated using two clinical DDI studies (Kashuba 1998, Lam 2003).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
2007 CYP3A4 Fluvoxamine / midazolam Fluvoxamine: titrated to a daily dose of 150 mg (50 mg in the morning (6 a.m.), 50 mg in the evening (8 p.m.))
Midazolam: 0.025 mg/kg iv single dose, 3 hours after a morning fluvoxamine dose		 Observed data:
Baseline (control) assessment: mean of six measures (every 2 weeks)
Phenotyping (fluvoxamine treatment) assessment: mean of two measures (14 days and 28 days after the start of fluvoxamine treatment), midazolam administered at 9 a.m.
Simulated: the midazolam dose was administered 3 weeks after the start of fluvoxamine as an approximation of the two observed assessments		 Kashuba 1998
1089 CYP3A4 Fluvoxamine / midazolam Fluvoxamine: titrated to a daily dose of 200 mg (100 mg BID)
Midazolam: 10 mg po single dose, 1 hour after a fluvoxamine steady state dose		 Lam 2003

1.2.25 Itraconazole - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Itraconazole-Alprazolam-DDI/releases/tag/v1.3

The itraconazole / alprazolam interaction was evaluated using one clinical DDI study (Yasui 1998).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1026 CYP3A4 Itraconazole / alprazolam Itraconazole: 200 mg po once daily (6 doses, capsule fasted)
Alprazolam: 0.8 mg po single dose, 1 hour after 4th itraconazole dose		 Yasui 1998

1.2.26 Itraconazole - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Itraconazole-Midazolam-DDI/releases/tag/v1.3

The itraconazole / midazolam interaction was evaluated using seven clinical DDI studies including 12 different clinical settings (Ahonen 1995, Backman 1998, Olkkola 1994, Olkkola 1996, Prueksaritanont 2017, Templeton 2010, Yu 2004).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
50 CYP3A4 Itraconazole / midazolam Itraconazole: 100 mg po once daily (4 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, simultaneous with 4th itraconazole dose		 Ahonen 1995
58 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (4 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, 2 hours after 4th itraconazole dose		 Midazolam simulated as 15 mg for comparability to control phase, in which a 15 mg dose was given. Backman 1998
59 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (4 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, 4 days after 4th itraconazole dose		 Midazolam simulated as 15 mg for comparability to control phase, in which a 15 mg dose was given. Backman 1998
370 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (4 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, 1 hours after 4th itraconazole dose		 Olkkola 1994
377 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (6 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, 2 hours after 1st itraconazole dose		 Olkkola 1996
378 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (6 doses, capsule fasted)
Midazolam: 0.05 mg/kg iv single dose, 2 hours after 4th itraconazole dose		 Olkkola 1996
379 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (6 doses, capsule fasted)
Midazolam: 7.5 mg po single dose, 2 hours after 6th itraconazole dose		 Olkkola 1996
1097 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (5 doses) (solution fasted)
Midazolam: 10 µg po single dose, simultaneous with 4th itraconazole dose		 Prueksaritanont 2017
424 CYP3A4 Itraconazole / midazolam Itraconazole: 50 mg po single dose (solution fasted)
Midazolam: 2 mg po single dose, 4 hours after itraconazole dose		 Templeton 2010
425 CYP3A4 Itraconazole / midazolam Itraconazole: 100 mg po single dose (solution fasted)
Midazolam: 2 mg po single dose, 4 hours after itraconazole dose		 Templeton 2010
426 CYP3A4 Itraconazole / midazolam Itraconazole: 400 mg po single dose (solution fasted)
Midazolam: 2 mg po single dose, 4 hours after itraconazole dose		 Templeton 2010
199 CYP3A4 Itraconazole / midazolam Itraconazole: 200 mg po once daily (4 doses, capsule fasted)
Midazolam: 1 mg iv single dose, simultaneous with4th itraconazole dose		 Only assessment in CYP3A5*3/*3 genotype subjects simulated. Yu 2004

1.2.27 Itraconazole-Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Itraconazole-Triazolam-DDI/releases/tag/v1.2

The itraconazole / triazolam interaction was evaluated using two clinical DDI studies including 5 different clinical settings (Neuvonen 1996, Varhe 1994).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1078 CYP3A4 Itraconazole / triazolam Itraconazole: 200 mg po single dose (capsule fasted)
triazolam: 0.25 mg po single dose, simultaneous with itraconazole dose		 3 hours fasting before triazolam/itraconazole administration Neuvonen 1996
1079 CYP3A4 Itraconazole / triazolam Itraconazole: 200 mg po single dose (capsule fed)
triazolam: 0.25 mg po single dose, 3 hours after itraconazole dose		 itraconazole dose was taken after lunch Neuvonen 1996
1080 CYP3A4 Itraconazole / triazolam Itraconazole: 200 mg po single dose (capsule fed)
triazolam: 0.25 mg po single dose, 12 hours after itraconazole dose		 itraconazole dose was taken with a snack, 3 hours fasting before triazolam administration Neuvonen 1996
1081 CYP3A4 Itraconazole / triazolam Itraconazole: 200 mg po single dose (capsule fed)
triazolam: 0.25 mg po single dose, 24 hours after itraconazole dose		 itraconazole dose was taken with a snack, 3 hours fasting before triazolam administration Neuvonen 1996
1029 CYP3A4 Itraconazole / triazolam Itraconazole: 200 mg po once daily (4 doses, capsule fasted)
triazolam: 0.25 mg po single dose, 1 hour after 4th itraconazole dose		 Varhe 1994

1.2.28 Rifampicin - Alfentanil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Rifampicin-Alfentanil-DDI/releases/tag/v1.2

The rifampicin / alfentanil interaction was evaluated using 5 clinical DDI studies including 16 different clinical settings (Kharasch 1997, Kharasch 2004, Kharasch 2011, Kharasch 2011b, Phimmasone 2001).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
278 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (5 doses)
Alfentanil: 20 µg/kg IV single dose, 24.5 h after 5th rifampicin dose		 Kharasch 1997
283 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 15 µg/kg IV single dose, 9 h after 5th rifampicin dose		 Kharasch 2004
288 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 60 µg/kg PO single dose, 9 h after 6th rifampicin dose		 Kharasch 2004
299 CYP3A4 Rifampicin / alfentanil Rifampicin: 5 mg po once daily (6 doses)
Alfentanil: 15 µg/kg IV single dose, 13 h after 5th rifampicin dose		 Kharasch 2011
300 CYP3A4 Rifampicin / alfentanil Rifampicin: 10 mg po once daily (6 doses)
Alfentanil: 15 µg/kg IV single dose, 13 h after 5th rifampicin dose		 Kharasch 2011
301 CYP3A4 Rifampicin / alfentanil Rifampicin: 25 mg po once daily (6 doses)
Alfentanil: 15 µg/kg IV single dose, 13 h after 5th rifampicin dose		 Kharasch 2011
302 CYP3A4 Rifampicin / alfentanil Rifampicin: 75 mg po once daily (6 doses)
Alfentanil: 15 µg/kg IV single dose, 13 h after 5th rifampicin dose		 Kharasch 2011
309 CYP3A4 Rifampicin / alfentanil Rifampicin: 5 mg po once daily (6 doses)
Alfentanil: 75 µg/kg PO single dose, 13 h after 6th rifampicin dose		 Kharasch 2011
310 CYP3A4 Rifampicin / alfentanil Rifampicin: 10 mg po once daily (6 doses)
Alfentanil: 75 µg/kg PO single dose, 13 h after 6th rifampicin dose		 Kharasch 2011
311 CYP3A4 Rifampicin / alfentanil Rifampicin: 25 mg po once daily (6 doses)
Alfentanil: 75 µg/kg PO single dose, 13 h after 6th rifampicin dose		 Kharasch 2011
312 CYP3A4 Rifampicin / alfentanil Rifampicin: 75 mg po once daily (6 doses)
Alfentanil: 75 µg/kg PO single dose, 13 h after 6th rifampicin dose		 Kharasch 2011
763 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 1 mg IV single dose, 12 h after 5th rifampicin dose		 sequential administration of intravenous unlabeled alfentanil and oral deuterated alfentanil Kharasch 2011b
771 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 4 mg PO single dose, 15 h after 5th rifampicin dose		 sequential administration of intravenous unlabeled alfentanil and oral deuterated alfentanil Kharasch 2011b
767 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 1 mg IV single dose, 12 h after 6th rifampicin dose		 simultaneous administration of intravenous unlabeled alfentanil and oral deuterated alfentanil Kharasch 2011b
775 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (6 doses)
Alfentanil: 4 mg PO single dose, 12 h after 6th rifampicin dose		 simultaneous administration of intravenous unlabeled alfentanil and oral deuterated alfentanil Kharasch 2011b
391 CYP3A4 Rifampicin / alfentanil Rifampicin: 600 mg po once daily (5 doses)
Alfentanil: 15 µg/kg IV single dose, 11 h after 5th rifampicin dose		 Phimmasone 2001

1.2.29 Rifampicin - Alprazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Rifampicin-Alprazolam-DDI/releases/tag/v1.2

The rifampicin-alprazolam interaction was evaluated using two clinical DDI studies quantifying the interaction in three clinical settings (Gashaw 2003, Schmider 1999).

DataID Enzyme Perpetrator / victim Study design Comments Clinical study
2009 CYP3A4 Rifampicin / alprazolam Rifampicin: 450 mg, five doses at irregular times intervals over 4 days
Alprazolam: 1 mg po single dose, 14 hours after the last rifampicin dose		 Gashaw 2003
2010 CYP3A4 Rifampicin / alprazolam Rifampicin: 450 mg, five doses at irregular times intervals over 4 days followed by a wash-out phase for 14 days
Alprazolam: 1 mg po single dose after the wash-out phase (i.e. 350 hours after the last rifampicin dose)		 Gashaw 2003
1001 CYP3A4 Rifampicin / alprazolam Rifampicin: 450 mg po QD for 4 days
Alprazolam: 1 mg po single dose, 24 hours after the last rifampicin dose		 Administration time of alprazolam relative to rifampin not reported; it was assumed that alprazolam was administered 24h after the last rifampin dose Schmider 1999

1.2.30 Rifampicin - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Rifampicin-Midazolam-DDI/releases/tag/v1.3

The rifampicin / midazolam interaction was evaluated using 24 clinical DDI studies including 43 different clinical settings (Backman 1996, Backman 1998, Björkhem-Bergman 2013, Chattopadhyay 2018,Chung 2006, Eap 2004, Gorski 2003, Gurley 2006, Gurley 2008a, Kharasch 1997, Kharasch 2004, Kharasch 2011, Kim 2018, Link 2008, Lutz 2018, Phimmasone 2001, Prueksaritanont 2017, Reitman 2011, Shin 2013, Shin 2016, Szalat 2007, van Dyk 2018, Wiesinger 2011, Yu 2004).

In the study by Eap 2004, the induction of CYP3A4 by rifampicin was evaluated using first 0.075 mg and one day later 7.5 and orally administered midazolam. The magnitude of the DDI with the low dose was much lower than for the higher dose (AUC ratio 0.44 vs. 0.09), which can actually only be explained by issues with the limit of detection after induction for the small midazolam dose considering the entire set of observed data. Therefore, as well as in Almond 2016, the dataset of the low dose setting was excluded from this analysis.

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
54 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (5 doses)
Midazolam: 15 mg PO single dose, 17 h after 5th rifampicin dose		 Backman 1996
56 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (5 doses)
Midazolam: 15 mg PO single dose, 17 h after 5th rifampicin dose (Phase IV)		 Backman 1998
57 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (5 doses)
Midazolam: 15 mg PO single dose, 7 days after 5th rifampicin dose (Phase V)		 Backman 1998
1355 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (14 doses)
Midazolam: 4 mg PO single dose, 1 day after 14th rifampicin dose		 Björkhem-Bergman 2013
1356 CYP3A4 Rifampicin / midazolam Rifampicin: 20 mg po once daily (14 doses)
Midazolam: 4 mg PO single dose, 1 day after 14th rifampicin dose		 Björkhem-Bergman 2013
1357 CYP3A4 Rifampicin / midazolam Rifampicin: 100 mg po once daily (14 doses)
Midazolam: 4 mg PO single dose, 1 day after 14th rifampicin dose		 Björkhem-Bergman 2013
1362 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily morning administrations (11 doses), 8th dose of rifampicin was taken in the evening (12 h after intake of midazolam)
Midazolam: 1 mg PO single dose on day 8 (24 hours after the 7th rifampicin dose)		 Subjects received a single dose of vilaprisan 4 mg simultaneously with midazolam (in both phases). Chattopadhyay 2018
113 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (9 doses)
Midazolam: 0.075 mg/kg PO single dose, 22 h after 7th rifampicin dose		 Chung 2006
129 CYP3A4 Rifampicin / midazolam Rifampicin: 450 mg po once daily (5 doses)
Midazolam: 0.075 mg PO single dose, 18 h after 4th rifampicin dose		 Dataset excluded (see comment above) Eap 2004
132 CYP3A4 Rifampicin / midazolam Rifampicin: 450 mg po once daily (5 doses)
Midazolam: 7.5 mg PO single dose, 18 h after 5th rifampicin dose		 Eap 2004
179 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (7 doses)
Midazolam: 0.05 mg/kg IV single dose, 12 h after 6th rifampicin dose		 Gorski 2003
177 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (7 doses)
Midazolam: 6 mg PO single dose, 12 h after 6th rifampicin dose		 Subjects received a 4 mg midazolam dose in control phase. Gorski 2003
215 CYP3A4 Rifampicin / midazolam Rifampicin: 300 mg po twice daily (14 doses, 7 days)
Midazolam: 8 mg PO single dose, 2 h after 13th rifampicin dose		 Gurley 2006
221 CYP3A4 Rifampicin / midazolam Rifampicin: 300 mg po twice daily (14 doses, 7 days)
Midazolam: 8 mg PO single dose, 2 h after 13th rifampicin dose		 Gurley 2008a
276 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (5 doses)
Midazolam: 1 mg IV single dose, 24 h after 5th rifampicin dose		 Kharasch 1997
280 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (6 doses)
Midazolam: 1 mg IV single dose, 8 h after 5th rifampicin dose		 Kharasch 2004
286 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (6 doses)
Midazolam: 3 mg PO single dose, 8 h after 6th rifampicin dose		 Kharasch 2004
294 CYP3A4 Rifampicin / midazolam Rifampicin: 5 mg po once daily (6 doses)
Midazolam: 1 mg IV single dose, 12 h after 5th rifampicin dose		 Kharasch 2011
295 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (6 doses)
Midazolam: 1 mg IV single dose, 12 h after 5th rifampicin dose		 Kharasch 2011
296 CYP3A4 Rifampicin / midazolam Rifampicin: 25 mg po once daily (6 doses)
Midazolam: 1 mg IV single dose, 12 h after 5th rifampicin dose		 Kharasch 2011
297 CYP3A4 Rifampicin / midazolam Rifampicin: 75 mg po once daily (6 doses)
Midazolam: 1 mg IV single dose, 12 h after 5th rifampicin dose		 Kharasch 2011
304 CYP3A4 Rifampicin / midazolam Rifampicin: 5 mg po once daily (6 doses)
Midazolam: 3 mg PO single dose, 12 h after 6th rifampicin dose		 Kharasch 2011
305 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (6 doses)
Midazolam: 3 mg PO single dose, 12 h after 6th rifampicin dose		 Kharasch 2011
306 CYP3A4 Rifampicin / midazolam Rifampicin: 25 mg po once daily (6 doses)
Midazolam: 3 mg PO single dose, 12 h after 6th rifampicin dose		 Kharasch 2011
307 CYP3A4 Rifampicin / midazolam Rifampicin: 75 mg po once daily (6 doses)
Midazolam: 3 mg PO single dose, 12 h after 6th rifampicin dose		 Kharasch 2011
2036 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (10 doses)
Midazolam: 2.5 mg IV single dose, simultaneous with 10th rifampicin dose		 Only assessment in male subjects simulated.
Subjects received a 1 mg midazolam dose in control phase. Observed reported dose-normalized AUCR back-calculated to non dose-normalized AUCR.		 Kim 2018
342 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (6 doses)
Midazolam: 2 mg IV single dose, 24 h after 6th rifampicin dose		 Link 2008
344 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (6 doses)
Midazolam: 7.5 mg PO single dose, 24 h after 6th rifampicin dose		 Link 2008
1350 CYP3A4 Rifampicin / midazolam Rifampicin: 2 mg po once daily (18 doses)
Midazolam: 2 mg PO single dose, 12 h after 10th rifampicin dose		 Cohort2,
Cocktail study		 Lutz 2008
1351 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (18 doses)
Midazolam: 2 mg PO single dose, 12 h after 10th rifampicin dose		 Cohort 1,
Cocktail study		 Lutz 2008
1352 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (18 doses), then 75 mg po once daily (18 doses)
Midazolam: 2 mg PO single dose, 12 h after 10th 75 mg rifampicin dose		 Cohort 1,
Cocktail study		 Lutz 2008
1353 CYP3A4 Rifampicin / midazolam Rifampicin: 2 mg po once daily (18 doses), then 600 mg po once daily (18 doses)
Midazolam: 2 mg PO single dose, 12 h after 10th 600mg rifampicin dose		 Cohort 2,
Cocktail study		 Lutz 2008
389 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (5 doses)
Midazolam: 1 mg IV single dose, 10 h after 5th rifampicin dose		 Phimmasone 2001
1098 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po SD
Midazolam: 10 µg PO single dose, simultaneous with rifampicin dose		 Prueksaritanont 2017
392 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (4 weeks)
Midazolam: 2 mg PO single dose, simultaneous with 28th rifampicin dose		 PK data of midazolam administered 28 days after the last rifampicin dose served as control (reference) Reitman 2011
393 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (4 weeks)
Midazolam: 2 mg PO single dose, 7 days after 28th rifampicin dose		 PK data of midazolam administered 28 days after the last rifampicin dose served as control (reference) Reitman 2011
394 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (4 weeks)
Midazolam: 2 mg PO single dose, 14 days after 28th rifampicin dose		 PK data of midazolam administered 28 days after the last rifampicin dose served as control (reference) Reitman 2011
1092 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (10 doses)
Midazolam: 2.5 mg IV single dose, simultaneous h with 10th rifampicin dose		 Subjects received a 1 mg midazolam dose in control phase. Observed reported dose-normalized AUCR back-calculated to non dose-normalized AUCR. Shin 2013
1095 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (10 doses)
Midazolam: 2.5 mg IV single dose, simultaneous h with 10th rifampicin dose		 Subjects received a 1 mg midazolam dose in control phase. Observed reported dose-normalized AUCR back-calculated to non dose-normalized AUCR. Shin 2016
422 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (7 doses)
Midazolam: 0.05 mg/kg IV single dose, 12 h after 12th rifampicin dose		 Szalat 2007
2002 CYP3A4 Rifampicin / midazolam Rifampicin: 300 mg po once daily (7 doses)
Midazolam: 1 mg PO single dose, 12 h after 7th rifampicin dose		 Only assessment in Caucasian subjects simulated.
AUC0-6h ratio reported and simulated for comparison.		 van Dyk 2018
204 CYP3A4 Rifampicin / midazolam Rifampicin: 10 mg po once daily (11 doses)
Midazolam: 1 mg PO single dose, 12 h after 8th rifampicin dose		 In the study midazolam was coadministered with either etonogestrel, dienogest, drospirenone, levonorgestrel or norethindrone. Wiesinger 2020
205 CYP3A4 Rifampicin / midazolam Rifampicin: 11 doses of 10 mg po once daily, followed by 11 doses of 600 mg po once daily
Midazolam: 1 mg PO single dose, 12 h after 8th 600 mg rifampicin dose (after the 19th overall rifampicin dose)		 In the study midazolam was coadministered with either etonogestrel, dienogest, drospirenone, levonorgestrel or norethindrone. Wiesinger 2020
202 CYP3A4 Rifampicin / midazolam Rifampicin: 600 mg po once daily (10 doses)
Midazolam: 2 mg IV single dose, 24 h after 10th rifampicin dose		 Only assessment in CYP3A5*3/*3 genotype subjects simulated.
Subjects received a 1 mg midazolam dose in control phase. Observed reported dose-normalized AUCR back-calculated to non dose-normalized AUCR.		 Yu 2004

1.2.31 Rifampicin - Triazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Rifampicin-Triazolam-DDI/releases/tag/v1.2

The rifampicin-triazolam interaction was evaluated using one clinical DDI study (Villikka 1997).

DataID Enzyme Perpetrator / victim Study design Comments Clinical study
1004 CYP3A4 Rifampicin / triazolam Rifampicin: 600 mg QD for 5 days
Triazolam: 0.5 mg po single dose, 17 hours after the last rifampicin dose		 Villikka 1997

1.2.32 Rifampicin - Verapamil DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Rifampicin-Verapamil-DDI/releases/tag/v2.0

The rifampicin / verapamil interaction was evaluated using 1 clinical DDI study including 2 different clinical settings (Barbarash 1988).

DataID Enzyme, Transporter Perpetrator / victim Study design Comments Clinical study
2056 CYP3A4,
P-gp		 Rifampicin / verapamil Rifampicin: 600 mg QD for 15 days
Verapamil: 10 mg iv single dose, 12 hours after the 13th rifampicin dose		 Barbarash 1988
2058 CYP3A4,
P-gp		 Rifampicin / verapamil Rifampicin: 600 mg QD for 15 days
Verapamil: 120 mg po single dose, 12 hours after the 15th rifampicin dose		 Barbarash 1988

1.2.33 Verapamil - Midazolam DDI

The release of the snapshot containing the respective simulations can be found here: https://github.com/Open-Systems-Pharmacology/Verapamil-Midazolam-DDI/releases/tag/v2.0

The verapamil / midazolam interaction was evaluated using two clinical DDI studies including 3 different clinical settings (Backman 1994, Wang 2005).

DataID Enzyme Perpetrator / victim Study design Comment Clinical study
1108 CYP3A4 Verapamil / midazolam Verapamil: 80 mg po three times a day (5 doses)
Midazolam: 15 mg po single dose, 1 hours after 4th verapamil dose		 Backman 1994
1111 CYP3A4 Verapamil / midazolam Verapamil: 240 mg po once daily (7 doses, sustained release)
Midazolam: 0.05 mg/kg iv single dose, 24 hours after the 7th verapamil dose		 Wang 2005
1116 CYP3A4 Verapamil / midazolam Verapamil: 240 mg po once daily (7 doses, sustained release)
Midazolam: 4 mg po single dose, 48 hours after the 7th verapamil dose		 Wang 2005

2 Qualification of Use Case CYP3A4-mediated DDI

The following section shows the correlations between observed and model-predicted AUC and Cmax ratios, respectively.

Specifically, the PBPK model performance for the PK parameters AUC ratio (AUCR) and Cmax ratio (CMAXR) is assessed via:

  • predicted (Pred) vs. observed (Obs) plots

  • Pred/Obs vs. Obs plots

  • geometric mean fold error (GMFE):

GMFE equation

  • number of AUCR and CMAXR falling within 2-fold error range and within the limits as suggested by Guest et al. 2011

  • detailed table of results for each study

In the plots,

  • the dotted lines denote 0.50–2.00 (2-fold) criterion,

  • the solid lines denote the limits as suggested by Guest et al. 2011,

  • the bold solid line denotes the unity line,

  • each color represents one combination of drugs,

  • squares represent studies with intravenous administration of the victim drug and circles represent studies with oral administration of the victim drug.

Figure 2-1: CYP3A4 DDI. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-2: CYP3A4 DDI. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-3: CYP3A4 DDI. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-4: CYP3A4 DDI. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-1: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.36
CMAX 1.32



Table 2-2: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 172 -
Points within Guest et al. 120 69.77
Points within 2 fold 154 89.53



Table 2-3: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 116 -
Points within Guest et al. 66 56.90
Points within 2 fold 106 91.38



Table 2-4: Summary table for CYP3A4 DDI

DataID Perpetrator Victim Predicted AUC Ratio Observed AUC Ratio Pred/Obs AUC Ratio Predicted CMAX Ratio Observed CMAX Ratio Pred/Obs CMAX Ratio Reference
50 Itraconazole, 100 mg, PO, MD OD (4 days) Midazolam, PO 3.48 5.75 0.61 1.96 2.56 0.77 Ahonen 1995
54 Rifampicin, 600 mg, PO, MD OD (5 days) Midazolam, PO 0.04 0.04 0.94 0.10 0.06 1.59 Backman 1996
56 Rifampicin, 600 mg, PO, MD OD (5 days) Midazolam, PO 0.04 0.02 1.67 0.10 0.05 1.82 Backman 1998
57 Rifampicin, 600 mg, PO, MD OD (5 days) Midazolam, PO 0.12 0.13 0.95 0.23 0.20 1.15 Backman 1998
58 Itraconazole, 200 mg, PO, MD OD (4 days) Midazolam, PO 4.88 7.97 0.61 2.23 3.12 0.71 Backman 1998
59 Itraconazole, 200 mg, PO, MD OD (4 days) Midazolam, PO 1.13 2.63 0.43 1.07 1.92 0.56 Backman 1998
113 Rifampicin, 600 mg, PO, MD OD (9 days) Midazolam, PO 0.03 0.12 0.23 0.07 0.17 0.42 Chung 2006
132 Rifampicin, 450 mg, PO, MD OD (5 days) Midazolam, PO 0.03 0.05 0.65 0.09 0.11 0.77 Eap 2004
173 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, PO 9.22 7.14 1.29 3.08 - - Gorski 1998
175 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, IV 3.07 2.67 1.15 1.24 - - Gorski 1998
177 Rifampicin, 600 mg, PO, MD OD (7 days) Midazolam, PO 0.05 0.10 0.46 0.12 0.10 1.17 Gorski 2003
179 Rifampicin, 600 mg, PO, MD OD (7 days) Midazolam, IV 0.49 0.45 1.09 0.75 - - Gorski 2003
199 Itraconazole, 200 mg, PO, MD OD (4 days) Midazolam, IV 2.46 3.33 0.74 1.01 - - Yu 2004
202 Rifampicin, 600 mg, PO, MD OD (10 days) Midazolam, IV 0.84 0.83 1.00 1.89 - - Yu 2004
204 Rifampicin, 10 mg, PO, MD OD (22 days) Midazolam, PO 0.27 0.54 0.50 0.40 0.63 0.63 Wiesinger 2020
205 Rifampicin, 600 mg, PO, MD OD (22 days) Midazolam, PO 0.03 0.14 0.22 0.07 0.19 0.36 Wiesinger 2020
215 Rifampicin, 300 mg, PO, MD BID (7 days) Midazolam, PO 0.04 0.06 0.77 0.11 0.12 0.90 Gurley 2006
217 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, PO 7.69 8.39 0.92 2.74 3.80 0.72 Gurley 2006
221 Rifampicin, 300 mg, PO, MD BID (7 days) Midazolam, PO 0.04 0.06 0.73 0.11 0.11 1.01 Gurley 2008a
223 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, PO 7.69 5.48 1.40 2.74 2.17 1.26 Gurley 2008a
276 Rifampicin, 600 mg, PO, MD OD (5 days) Midazolam, IV 0.47 0.38 1.25 0.90 - - Kharasch 1997
278 Rifampicin, 600 mg, PO, MD OD (5 days) Alfentanil, IV 0.36 0.36 0.99 0.90 - - Kharasch 1997
280 Rifampicin, 600 mg, PO, MD OD (6 days) Midazolam, IV 0.48 0.52 0.91 0.91 1.01 0.90 Kharasch 2004
283 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, IV 0.49 0.38 1.30 1.20 1.00 1.20 Kharasch 2004
286 Rifampicin, 600 mg, PO, MD OD (6 days) Midazolam, PO 0.04 0.05 0.69 0.08 0.11 0.69 Kharasch 2004
288 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, PO 0.04 0.05 0.87 0.09 0.11 0.79 Kharasch 2004
294 Rifampicin, 5 mg, PO, MD OD (6 days) Midazolam, IV 0.78 0.84 0.93 0.98 1.03 0.95 Kharasch 2011
295 Rifampicin, 10 mg, PO, MD OD (6 days) Midazolam, IV 0.70 0.77 0.91 0.97 1.06 0.91 Kharasch 2011
296 Rifampicin, 25 mg, PO, MD OD (6 days) Midazolam, IV 0.60 0.63 0.96 0.95 0.84 1.13 Kharasch 2011
297 Rifampicin, 75 mg, PO, MD OD (6 days) Midazolam, IV 0.53 0.60 0.88 0.93 1.32 0.70 Kharasch 2011
299 Rifampicin, 5 mg, PO, MD OD (6 days) Alfentanil, IV 0.98 0.83 1.19 1.31 1.04 1.26 Kharasch 2011
300 Rifampicin, 10 mg, PO, MD OD (6 days) Alfentanil, IV 0.85 0.75 1.13 1.29 1.05 1.23 Kharasch 2011
301 Rifampicin, 25 mg, PO, MD OD (6 days) Alfentanil, IV 0.69 0.59 1.18 1.27 1.00 1.27 Kharasch 2011
302 Rifampicin, 75 mg, PO, MD OD (6 days) Alfentanil, IV 0.58 0.51 1.13 1.24 1.03 1.20 Kharasch 2011
304 Rifampicin, 5 mg, PO, MD OD (6 days) Midazolam, PO 0.42 0.80 0.53 0.55 0.80 0.69 Kharasch 2011
305 Rifampicin, 10 mg, PO, MD OD (6 days) Midazolam, PO 0.29 0.68 0.43 0.42 0.93 0.46 Kharasch 2011
306 Rifampicin, 25 mg, PO, MD OD (6 days) Midazolam, PO 0.16 0.40 0.41 0.27 0.51 0.54 Kharasch 2011
307 Rifampicin, 75 mg, PO, MD OD (6 days) Midazolam, PO 0.08 0.25 0.33 0.15 0.34 0.46 Kharasch 2011
309 Rifampicin, 5 mg, PO, MD OD (6 days) Alfentanil, PO 0.46 0.74 0.62 0.60 0.86 0.69 Kharasch 2011
310 Rifampicin, 10 mg, PO, MD OD (6 days) Alfentanil, PO 0.32 0.61 0.53 0.47 0.86 0.54 Kharasch 2011
311 Rifampicin, 25 mg, PO, MD OD (6 days) Alfentanil, PO 0.19 0.30 0.62 0.31 0.49 0.64 Kharasch 2011
312 Rifampicin, 75 mg, PO, MD OD (6 days) Alfentanil, PO 0.10 0.13 0.74 0.18 0.25 0.72 Kharasch 2011
342 Rifampicin, 600 mg, PO, MD OD (6 days) Midazolam, IV 0.47 0.66 0.72 0.90 1.11 0.82 Link 2008
344 Rifampicin, 600 mg, PO, MD OD (6 days) Midazolam, PO 0.03 0.02 1.97 0.08 0.03 2.23 Link 2008
354 Clarithromycin, 500 mg, PO, MD BID (4 days) Midazolam, PO 6.07 5.56 1.09 2.62 - - Markert 2013
362 Erythromycin, 200 mg, PO, MD QID (2 days) Midazolam, PO 1.31 1.16 1.13 0.82 0.91 0.90 Okudaira 2007
363 Erythromycin, 200 mg, PO, MD QID (4 days) Midazolam, PO 1.67 1.69 0.99 0.93 1.20 0.77 Okudaira 2007
364 Erythromycin, 200 mg, PO, MD QID (7 days) Midazolam, PO 1.73 1.69 1.02 0.95 1.17 0.81 Okudaira 2007
366 Erythromycin, 500 mg, PO, MD TID (7 days) Midazolam, PO 3.86 4.07 0.95 1.89 2.70 0.70 Olkkola 1993
368 Erythromycin, 500 mg, PO, MD TID (7 days) Midazolam, IV 2.05 1.96 1.04 1.02 - - Olkkola 1993
370 Itraconazole, 200 mg, PO, MD OD (4 days) Midazolam, PO 5.28 10.80 0.49 2.24 3.40 0.66 Olkkola 1994
377 Itraconazole, 200 mg, PO, SD Midazolam, PO 4.49 3.40 1.32 2.20 1.80 1.22 Olkkola 1996
378 Itraconazole, 200 mg, PO, MD OD (4 days) Midazolam, IV 2.29 3.23 0.71 1.01 - - Olkkola 1996
379 Itraconazole, 200 mg, PO, MD OD (6 days) Midazolam, PO 6.24 6.60 0.95 2.57 2.50 1.03 Olkkola 1996
380 Fluconazole, 400 mg, PO, SD Midazolam, PO 2.71 2.50 1.08 2.19 2.50 0.88 Olkkola 1996
381 Fluconazole, 400/200 mg, PO, MD OD (4 days) Midazolam, IV 2.13 2.04 1.05 0.32 - - Olkkola 1996
382 Fluconazole, 400/200 mg, PO, MD OD (6 days) Midazolam, PO 4.20 3.60 1.17 2.25 1.70 1.32 Olkkola 1996
389 Rifampicin, 600 mg, PO, MD OD (5 days) Midazolam, IV 0.48 0.51 0.93 0.91 - - Phimmasone 2001
391 Rifampicin, 600 mg, PO, MD OD (5 days) Alfentanil, IV 0.36 0.55 0.66 0.90 - - Phimmasone 2001
392 Rifampicin, 600 mg, PO, MD OD (28 days) Midazolam, PO 0.21 0.12 1.67 0.27 0.16 1.66 Reitman 2011
393 Rifampicin, 600 mg, PO, MD OD (28 days) Midazolam, PO 0.37 0.38 0.98 0.51 0.40 1.27 Reitman 2011
394 Rifampicin, 600 mg, PO, MD OD (28 days) Midazolam, PO 0.92 0.81 1.13 0.95 0.73 1.30 Reitman 2011
420 Erythromycin, 500 mg, PO, MD QID (5 days) Midazolam, IV 2.36 1.60 1.48 1.03 - - Swart 2002
422 Rifampicin, 600 mg, PO, MD OD (7 days) Midazolam, IV 0.49 0.58 0.85 0.75 - - Szalat 2007
424 Itraconazole, 50 mg, PO, SD Midazolam, PO 3.26 2.00 1.63 2.20 - - Templeton 2010
425 Itraconazole, 200 mg, PO, SD Midazolam, PO 7.60 4.70 1.62 3.44 - - Templeton 2010
426 Itraconazole, 400 mg, PO, SD Midazolam, PO 9.74 5.40 1.80 3.73 - - Templeton 2010
465 Erythromycin, 500 mg, PO, MD Carbamazepine, PO 1.67 1.32 1.27 1.06 0.96 1.11 Barzaghi 1987
469 Clarithromycin, 250 mg, PO, MD BID (5 days) Midazolam, PO 2.38 3.57 0.67 1.59 2.44 0.65 Yeates 1996
471 Erythromycin, 500 mg, PO, MD TID (3 days) Midazolam, PO 4.85 3.81 1.27 2.21 2.71 0.81 Zimmermann 1996
757 Erythromycin, 333 mg, PO, MD TID (3 days) Triazolam, PO 3.87 2.06 1.88 2.11 1.46 1.44 Phillips 1986
763 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, IV 0.36 0.40 0.91 0.90 - - Kharasch 2011b
767 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, IV 0.36 0.40 0.89 0.90 - - Kharasch 2011b
771 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, PO 0.04 0.06 0.64 0.08 - - Kharasch 2011b
775 Rifampicin, 600 mg, PO, MD OD (6 days) Alfentanil, PO 0.04 0.06 0.62 0.08 - - Kharasch 2011b
777 Erythromycin, 400 mg, PO, MD TID (10 days) Alprazolam, PO 1.77 2.47 0.72 1.08 1.18 0.91 Yasui 1996
779 Erythromycin, 500 mg, PO, SD Alfentanil, IV 1.03 1.03 1.00 1.00 - - Bartkowski 1989
780 Erythromycin, 500 mg, PO, MD BID (6 days) Alfentanil, IV 1.69 1.46 1.16 1.03 - - Bartkowski 1989
781 Erythromycin, 500 mg, PO, MD OD (2 days) Triazolam, PO 3.12 3.65 0.86 1.90 1.77 1.07 Greenblatt 1998a
801 Efavirenz, 600 mg, PO, MD OD (19 days) Alfentanil, PO 0.23 0.22 1.07 0.36 0.43 0.83 Kharasch 2012
803 Efavirenz, 600 mg, PO, MD OD (19 days) Alfentanil, IV 0.56 0.54 1.04 0.92 1.10 0.84 Kharasch 2012
828 Erythromycin, 250 mg, PO, SD Midazolam, PO 3.51 1.72 2.04 3.21 - - Carls 2014
829 Erythromycin, 1000 mg, PO, SD Midazolam, PO 4.07 4.99 0.81 3.63 - - Carls 2014
900 Cimetidine, 300 mg, PO, MD Carbamazepine, PO 1.07 1.25 0.85 1.01 - - Dalton 1985a
943 Carbamazepine, , PO, Midazolam, PO 0.25 0.28 0.89 0.39 0.44 0.89 Kanefendt 2023
959 Carbamazepine, 200/400 mg, PO, MD Efavirenz, PO 0.94 0.64 1.47 0.96 0.79 1.21 Ji 2008
961 Efavirenz, 600 mg, PO, MD Carbamazepine, PO 0.49 0.73 0.66 0.58 0.80 0.73 Ji 2008
1001 Rifampicin, 450 mg, PO, MD OD (4 days) Alprazolam, PO 0.20 0.12 1.70 0.69 0.64 1.08 Schmider 1999
1004 Rifampicin, 600 mg, PO, MD OD (5 days) Triazolam, PO 0.03 0.05 0.65 0.11 0.12 0.93 Villikka 1997
1026 Itraconazole, 200 mg, PO, MD OD (6 days) Alprazolam, PO 2.29 2.66 0.86 1.10 1.29 0.85 Yasui 1998
1029 Itraconazole, 200 mg, PO, MD OD (4 days) Triazolam, PO 6.32 19.03 0.33 2.53 2.69 0.94 Varhe 1994
1078 Itraconazole, 200 mg, PO, SD Triazolam, PO 4.22 3.11 1.36 1.98 1.41 1.40 Neuvonen 1996
1079 Itraconazole, 200 mg, PO, SD Triazolam, PO 5.59 4.79 1.17 2.42 1.76 1.38 Neuvonen 1996
1080 Itraconazole, 200 mg, PO, SD Triazolam, PO 2.25 4.63 0.49 1.67 1.76 0.95 Neuvonen 1996
1081 Itraconazole, 200 mg, PO, SD Triazolam, PO 2.10 3.82 0.55 1.39 1.71 0.81 Neuvonen 1996
1089 Fluvoxamine, 50/100 mg, PO, MD OD (12 days), titrated from 50 mg BID to 100 mg BID administered for 6 days Midazolam, PO 1.40 1.66 0.85 1.20 1.63 0.74 Lam 2003
1092 Rifampicin, 600 mg, PO, MD OD (10 days) Midazolam, IV 1.18 1.15 1.03 2.26 - - Shin 2013
1095 Rifampicin, 600 mg, PO, MD OD (10 days) Midazolam, IV 1.18 1.23 0.97 2.26 1.77 1.27 Shin 2016
1097 Itraconazole, 200 mg, PO, MD OD (5 days) Midazolam, PO 19.36 7.04 2.75 4.67 3.71 1.26 Prueksaritanont 2017
1098 Rifampicin, 600 mg, PO, SD Midazolam, PO 2.24 0.94 2.39 1.88 1.30 1.45 Prueksaritanont 2017
1099 Clarithromycin, 500 mg, PO, MD BID (5 days) Midazolam, PO 7.83 4.84 1.62 3.18 2.69 1.18 Prueksaritanont 2017
1102 Clarithromycin, 500 mg, PO, MD OD (2 days) Triazolam, PO 3.58 5.06 0.71 2.01 1.97 1.02 Greenblatt 1998a
1104 Fluvoxamine, 50/100 mg, PO, MD OD (10 days), 50 mg day 1-3, then 100 mg Alprazolam, PO 1.01 1.26 0.80 1.01 1.18 0.85 Fleishaker 1994
1108 Verapamil, 80 mg, PO, MD TID (2 days) Midazolam, PO 2.22 2.92 0.76 1.57 1.97 0.80 Backman 1994
1111 Verapamil, 240 mg, PO, MD OD (7 days) Midazolam, IV 1.94 1.45 1.33 1.15 - - Wang 2005
1113 Fluvoxamine, 50/100 mg, PO, MD OD (10 days), 50 mg day 1-3, then 100 mg Alprazolam, PO 1.03 1.96 0.52 1.02 1.86 0.55 Fleishaker 1994
1116 Verapamil, 240 mg, PO, MD OD (7 days) Midazolam, PO 4.17 3.51 1.19 2.10 - - Wang 2005
1133 Carbamazepine, , PO, Midazolam, PO 0.26 0.32 0.81 0.40 0.46 0.89 Kanefendt 2023
1154 Erythromycin, 250 mg, PO, MD Carbamazepine, PO 1.46 1.24 1.18 1.05 - - Wong 1983
1157 Erythromycin, 250 mg, PO, MD QID (3 days) Carbamazepine, PO 1.24 1.27 0.98 1.18 1.09 1.08 Miles 1989
1158 Erythromycin, 250 mg, PO, MD QID (3 days) Carbamazepine, PO 1.25 1.42 0.88 1.18 1.00 1.18 Miles 1989
1319 Cimetidine, 300 mg, PO, MD QID (2 days) Midazolam, IV 1.08 0.89 1.21 1.00 - - Greenblatt 1986
1321 Cimetidine, 300 mg, PO, MD QID (2 days) Midazolam, PO 1.37 1.13 1.21 1.23 1.06 1.16 Greenblatt 1986
1322 Cimetidine, 800 mg, PO, SD Midazolam, PO 1.88 1.50 1.26 1.50 - - Martinez 1999
1324 Cimetidine, 400 mg, PO, MD: BID (1 day), OD (1 day) Midazolam, PO 1.38 1.35 1.03 1.18 - - Fee 1987
1326 Cimetidine, 400 mg, PO, SD Midazolam, PO 1.17 1.36 0.86 1.16 1.37 0.85 Salonen 1986
1328 Cimetidine, 300 mg, PO, MD QID (9 days) Verapamil, IV 1.00 0.71 1.41 1.00 0.96 1.04 Smith 1984
1330 Cimetidine, 300 mg, PO, MD QID (9 days) Verapamil, PO 1.03 1.37 0.75 1.09 1.13 0.96 Smith 1984
1332 Cimetidine, 300 mg, PO, MD QID (1 day) Alprazolam, PO 1.05 1.58 0.67 1.02 1.03 0.98 Abernethy 1983
1334 Cimetidine, 300 mg, PO, MD QID (1 day) Triazolam, PO 1.80 1.54 1.17 1.52 1.20 1.26 Abernethy 1983
1336 Cimetidine, 300 mg, PO, MD QID (2 days) Triazolam, PO 1.82 1.32 1.38 1.52 1.39 1.10 Friedman 1988
1338 Cimetidine, 300 mg, PO, MD QID (1 day) Triazolam, intraduodenal 1.61 1.55 1.04 1.41 1.35 1.04 Cox 1986
1340 Cimetidine, 200/400 mg, PO, (200mg): MD TID (17 days); (400mg): OD (17 days) Alprazolam, PO 1.12 1.73 0.65 1.07 1.82 0.59 Pourbaix 1985
1342 Cimetidine, 200/400 mg, PO, (200mg): MD TID (17 days); (400mg): OD (17 days) Triazolam, PO 1.90 2.20 0.86 1.60 1.51 1.06 Pourbaix 1985
1344 Cimetidine, 1200 mg, IV, MD OD (2 days) Alfentanil, IV 1.53 2.80 0.55 1.02 - - Kienlen 1993
1346 Cimetidine, 200/400 mg, PO, (200mg): MD TID (1 day), OD (1 day); (400mg): OD (1 day) Midazolam, PO 1.06 2.02 0.53 1.05 2.38 0.44 Elliott 1984
1350 Rifampicin, 2 mg, PO, MD OD (18 days) Midazolam, PO 0.57 0.77 0.75 0.69 0.79 0.87 Lutz 2018a
1351 Rifampicin, 10 mg, PO, MD OD (18 days) Midazolam, PO 0.27 0.40 0.67 0.40 0.52 0.78 Lutz 2018a
1352 Rifampicin, first 10, then 75 mg, PO, MD OD (18 days 10 mg, then 18 days 75 mg) Midazolam, PO 0.07 0.09 0.79 0.15 0.15 0.98 Lutz 2018a
1353 Rifampicin, first 2, then 600 mg, PO, MD OD (18 days 2 mg, then 18 days 600 mg) Midazolam, PO 0.03 0.09 0.33 0.07 0.14 0.48 Lutz 2018a
1355 Rifampicin, 10 mg, PO, MD OD (14 days) Midazolam, PO 0.34 0.50 0.68 0.48 - - Björkhem-Bergman 2013
1356 Rifampicin, 20 mg, PO, MD OD (14 days) Midazolam, PO 0.23 0.38 0.59 0.35 - - Björkhem-Bergman 2013
1357 Rifampicin, 100 mg, PO, MD OD (14 days) Midazolam, PO 0.08 0.25 0.32 0.15 - - Björkhem-Bergman 2013
1362 Rifampicin, 600 mg, PO, MD OD (11 days) Midazolam, PO 0.03 0.14 0.22 0.07 0.14 0.50 Chattopadhyay 2018
1392 Fluconazole, 400 mg, IV, SD Midazolam, PO 3.12 3.08 1.01 2.09 1.79 1.17 Ahonen 1997
1393 Fluconazole, 400 mg, PO, SD Midazolam, PO 3.41 3.41 1.00 2.19 2.30 0.95 Ahonen 1997
1394 Fluconazole, 50 mg, PO, MD for 4 days Triazolam, PO 1.79 1.59 1.13 1.37 1.47 0.94 Varhe 1996c
1395 Fluconazole, 100 mg, PO, MD for 4 days Triazolam, PO 2.72 1.99 1.36 1.76 1.40 1.26 Varhe 1996c
1396 Fluconazole, 200 mg, PO, MD for 4 days Triazolam, PO 4.14 3.65 1.13 2.16 2.33 0.93 Varhe 1996c
1398 Fluconazole, 400 mg, IV, SD Alfentanil, IV 2.21 2.07 1.07 1.01 1.20 0.84 Palkama 1998
1399 Fluconazole, 400 mg, PO, SD Alfentanil, IV 2.11 1.97 1.07 1.01 1.04 0.97 Palkama 1998
1457 Carbamazepine, 300 mg, PO, MD Alprazolam, PO 0.58 0.42 1.37 0.89 1.11 0.80 Furukori 1998
1460 Carbamazepine, 100, then escalated to 300 mg, PO, MD Midazolam, PO 0.23 0.21 1.09 0.37 0.32 1.16 Lutz 2018b
1464 Carbamazepine, 100/200/300 mg, PO, MD Midazolam, PO 0.28 0.28 0.98 0.42 0.40 1.06 Datta-Mannan 2024
1465 Carbamazepine, 100/200/300 mg, PO, MD Midazolam, PO 0.26 0.26 1.01 0.41 0.37 1.11 Datta-Mannan 2024
2002 Rifampicin, 300 mg, PO, MD OD (7 days) Midazolam, PO 0.04 0.26 0.16 0.08 0.38 0.22 van Dyk 2018
2004 Clarithromycin, 250 mg, PO, MD BID (3 days) Midazolam, PO 1.54 1.90 0.81 1.29 1.75 0.74 van Dyk 2018
2007 Fluvoxamine, 50/100 mg, PO, MD BID (4 weeks), dose titration to 150 mg/day over 7 days: 50 mg in the evening for 3 days, 50 mg in the morning and evening for the next 3 days, then 50 mg in the morning and 100 mg in the evening Midazolam, IV 1.04 1.50 0.69 1.00 - - Kashuba 1998
2009 Rifampicin, 450 mg, PO, MD OD (5 days) Alprazolam, PO 0.19 0.18 1.05 0.68 - - Gashaw 2003
2010 Rifampicin, 450 mg, PO, MD OD (5 days) Alprazolam, PO 0.97 0.92 1.06 1.00 - - Gashaw 2003
2027 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, IV 3.03 3.20 0.95 1.24 1.17 1.06 Quinney 2008
2030 Clarithromycin, 500 mg, PO, MD BID (7 days) Midazolam, PO 9.33 8.00 1.17 3.14 2.75 1.14 Quinney 2008
2036 Rifampicin, 600 mg, PO, MD OD (10 days) Midazolam, IV 1.18 1.15 1.03 2.26 - - Kim 2018
2041 Efavirenz, 400 mg, PO, MD OD (14 days) Midazolam, PO 0.11 0.10 1.11 0.24 0.18 1.32 Katzenmaier 2010
2044 Efavirenz, 400 mg, PO, SD Midazolam, PO 0.53 0.59 0.89 0.65 - - Mikus 2017
2045 Efavirenz, 400 mg, PO, SD Midazolam, IV 0.83 0.79 1.06 0.93 - - Mikus 2017
2047 Efavirenz, 400 mg, PO, SD Midazolam, PO 0.54 0.61 0.89 0.66 - - Mikus 2017
2048 Efavirenz, 400 mg, PO, SD Midazolam, IV 0.79 0.78 1.01 0.91 - - Mikus 2017
2049 Efavirenz, 400 mg, PO, SD Midazolam, PO 0.70 0.77 0.92 0.78 - - Mikus 2017
2050 Efavirenz, 400 mg, PO, SD Midazolam, IV 0.86 0.94 0.92 0.94 - - Mikus 2017
2051 Efavirenz, 400 mg, PO, SD Midazolam, PO 0.82 0.75 1.09 0.87 - - Mikus 2017
2052 Efavirenz, 400 mg, PO, SD Midazolam, IV 0.91 0.85 1.07 0.97 - - Mikus 2017
2053 Efavirenz, 400 mg, PO, SD Midazolam, PO 0.90 0.84 1.07 0.93 - - Mikus 2017
2054 Efavirenz, 400 mg, PO, SD Midazolam, IV 0.95 0.92 1.03 0.98 - - Mikus 2017
2056 Rifampicin, 600 mg, PO, MD OD (15 days) Verapamil, IV 0.69 0.82 0.84 0.96 - - Barbarash 1988
2058 Rifampicin, 600 mg, PO, MD OD (15 days) Verapamil, PO 0.08 0.07 1.20 0.12 0.04 3.21 Barbarash 1988
16149 Cimetidine, 300 mg, PO, MD QID Verapamil, IV 1.05 1.04 1.01 1.00 - - Abernethy et al. 1985
16150 Cimetidine, 300 mg, PO, MD QID Verapamil, PO 1.15 0.86 1.34 1.21 1.03 1.18 Abernethy et al. 1985
16151 Cimetidine, 400 mg, PO, MD BID R-Verapamil, PO 1.00 1.26 0.80 1.05 1.33 0.79 Mikus et al. 1990
16152 Cimetidine, 400 mg, PO, MD BID S-Verapamil, PO 1.00 1.41 0.71 1.05 1.83 0.57 Mikus et al. 1990
16155 Cimetidine, 400/200 mg, PO, MD QID (3times 200mg, fourth time 400mg) Verapamil, IV 1.00 1.07 0.93 1.00 - - Wing et al. 1985
16156 Cimetidine, 400/200 mg, PO, MD QID (3times 200mg, fourth time 400mg) Verapamil, PO 1.01 1.07 0.94 1.09 - - Wing et al. 1985



2.1 Mechanism

2.1.1 Induction

Figure 2-5: CYP3A4 DDI. Mechanism: Induction. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-6: CYP3A4 DDI. Mechanism: Induction. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-7: CYP3A4 DDI. Mechanism: Induction. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-8: CYP3A4 DDI. Mechanism: Induction. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-5: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.41
CMAX 1.42



Table 2-6: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 86 -
Points within Guest et al. 62 72.09
Points within 2 fold 74 86.05



Table 2-7: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 57 -
Points within Guest et al. 26 45.61
Points within 2 fold 48 84.21



2.1.2 Mechanism-based Inactivation

Figure 2-9: CYP3A4 DDI. Mechanism: Mechanism-based Inactivation. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-10: CYP3A4 DDI. Mechanism: Mechanism-based Inactivation. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-11: CYP3A4 DDI. Mechanism: Mechanism-based Inactivation. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-12: CYP3A4 DDI. Mechanism: Mechanism-based Inactivation. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-8: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.24
CMAX 1.22



Table 2-9: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 32 -
Points within Guest et al. 27 84.38
Points within 2 fold 31 96.88



Table 2-10: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 20 -
Points within Guest et al. 14 70
Points within 2 fold 20 100



2.1.3 Reversible Inhibition

Figure 2-13: CYP3A4 DDI. Mechanism: Reversible Inhibition. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-14: CYP3A4 DDI. Mechanism: Reversible Inhibition. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-15: CYP3A4 DDI. Mechanism: Reversible Inhibition. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-16: CYP3A4 DDI. Mechanism: Reversible Inhibition. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-11: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.37
CMAX 1.25



Table 2-12: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 54 -
Points within Guest et al. 31 57.41
Points within 2 fold 49 90.74



Table 2-13: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 39 -
Points within Guest et al. 26 66.67
Points within 2 fold 38 97.44



2.2 Perpetrator

2.2.1 Carbamazepine

Figure 2-17: CYP3A4 DDI. Perpetrator: Carbamazepine. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-18: CYP3A4 DDI. Perpetrator: Carbamazepine. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-19: CYP3A4 DDI. Perpetrator: Carbamazepine. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-20: CYP3A4 DDI. Perpetrator: Carbamazepine. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-14: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.18
CMAX 1.15



Table 2-15: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 7 -
Points within Guest et al. 6 85.71
Points within 2 fold 7 100.00



Table 2-16: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 7 -
Points within Guest et al. 5 71.43
Points within 2 fold 7 100.00



2.2.2 Cimetidine

Figure 2-21: CYP3A4 DDI. Perpetrator: Cimetidine. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-22: CYP3A4 DDI. Perpetrator: Cimetidine. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-23: CYP3A4 DDI. Perpetrator: Cimetidine. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-24: CYP3A4 DDI. Perpetrator: Cimetidine. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-17: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.27
CMAX 1.25



Table 2-18: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 22 -
Points within Guest et al. 9 40.91
Points within 2 fold 22 100.00



Table 2-19: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 14 -
Points within Guest et al. 6 42.86
Points within 2 fold 13 92.86



2.2.3 Clarithromycin

Figure 2-25: CYP3A4 DDI. Perpetrator: Clarithromycin. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-26: CYP3A4 DDI. Perpetrator: Clarithromycin. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-27: CYP3A4 DDI. Perpetrator: Clarithromycin. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-28: CYP3A4 DDI. Perpetrator: Clarithromycin. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-20: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.26
CMAX 1.23



Table 2-21: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 11 -
Points within Guest et al. 11 100
Points within 2 fold 11 100



Table 2-22: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 8 -
Points within Guest et al. 8 100
Points within 2 fold 8 100



2.2.4 Efavirenz

Figure 2-29: CYP3A4 DDI. Perpetrator: Efavirenz. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-30: CYP3A4 DDI. Perpetrator: Efavirenz. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-31: CYP3A4 DDI. Perpetrator: Efavirenz. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-32: CYP3A4 DDI. Perpetrator: Efavirenz. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-23: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.10
CMAX 1.27



Table 2-24: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 14 -
Points within Guest et al. 12 85.71
Points within 2 fold 14 100.00



Table 2-25: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 4 -
Points within Guest et al. 2 50
Points within 2 fold 4 100



2.2.5 Erythromycin

Figure 2-33: CYP3A4 DDI. Perpetrator: Erythromycin. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-34: CYP3A4 DDI. Perpetrator: Erythromycin. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-35: CYP3A4 DDI. Perpetrator: Erythromycin. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-36: CYP3A4 DDI. Perpetrator: Erythromycin. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-26: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.22
CMAX 1.20



Table 2-27: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 18 -
Points within Guest et al. 14 77.78
Points within 2 fold 17 94.44



Table 2-28: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 11 -
Points within Guest et al. 5 45.45
Points within 2 fold 11 100.00



2.2.6 Fluconazole

Figure 2-37: CYP3A4 DDI. Perpetrator: Fluconazole. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-38: CYP3A4 DDI. Perpetrator: Fluconazole. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-39: CYP3A4 DDI. Perpetrator: Fluconazole. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-40: CYP3A4 DDI. Perpetrator: Fluconazole. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-29: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.10
CMAX 1.14



Table 2-30: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 10 -
Points within Guest et al. 10 100
Points within 2 fold 10 100



Table 2-31: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 9 -
Points within Guest et al. 8 88.89
Points within 2 fold 9 100.00



2.2.7 Fluvoxamine

Figure 2-41: CYP3A4 DDI. Perpetrator: Fluvoxamine. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-42: CYP3A4 DDI. Perpetrator: Fluvoxamine. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-43: CYP3A4 DDI. Perpetrator: Fluvoxamine. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-44: CYP3A4 DDI. Perpetrator: Fluvoxamine. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-32: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.42
CMAX 1.43



Table 2-33: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 4 -
Points within Guest et al. 1 25
Points within 2 fold 4 100



Table 2-34: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 3 -
Points within Guest et al. 1 33.33
Points within 2 fold 3 100.00



2.2.8 Itraconazole

Figure 2-45: CYP3A4 DDI. Perpetrator: Itraconazole. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-46: CYP3A4 DDI. Perpetrator: Itraconazole. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-47: CYP3A4 DDI. Perpetrator: Itraconazole. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-48: CYP3A4 DDI. Perpetrator: Itraconazole. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-35: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.66
CMAX 1.28



Table 2-36: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 18 -
Points within Guest et al. 11 61.11
Points within 2 fold 13 72.22



Table 2-37: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 13 -
Points within Guest et al. 11 84.62
Points within 2 fold 13 100.00



2.2.9 Rifampicin

Figure 2-49: CYP3A4 DDI. Perpetrator: Rifampicin. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-50: CYP3A4 DDI. Perpetrator: Rifampicin. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-51: CYP3A4 DDI. Perpetrator: Rifampicin. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-52: CYP3A4 DDI. Perpetrator: Rifampicin. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-38: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.51
CMAX 1.48



Table 2-39: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 65 -
Points within Guest et al. 44 67.69
Points within 2 fold 53 81.54



Table 2-40: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 46 -
Points within Guest et al. 19 41.30
Points within 2 fold 37 80.43



2.2.10 Verapamil

Figure 2-53: CYP3A4 DDI. Perpetrator: Verapamil. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-54: CYP3A4 DDI. Perpetrator: Verapamil. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-55: CYP3A4 DDI. Perpetrator: Verapamil. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-56: CYP3A4 DDI. Perpetrator: Verapamil. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-41: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.28
CMAX 1.26



Table 2-42: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 3 -
Points within Guest et al. 2 66.67
Points within 2 fold 3 100.00



Table 2-43: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 1 -
Points within Guest et al. 1 100
Points within 2 fold 1 100



2.3 Victim

2.3.1 Alfentanil

Figure 2-57: CYP3A4 DDI. Victim: Alfentanil. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-58: CYP3A4 DDI. Victim: Alfentanil. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-59: CYP3A4 DDI. Victim: Alfentanil. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-60: CYP3A4 DDI. Victim: Alfentanil. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-44: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.27
CMAX 1.29



Table 2-45: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 23 -
Points within Guest et al. 18 78.26
Points within 2 fold 23 100.00



Table 2-46: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 14 -
Points within Guest et al. 4 28.57
Points within 2 fold 14 100.00



2.3.2 Alprazolam

Figure 2-61: CYP3A4 DDI. Victim: Alprazolam. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-62: CYP3A4 DDI. Victim: Alprazolam. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-63: CYP3A4 DDI. Victim: Alprazolam. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-64: CYP3A4 DDI. Victim: Alprazolam. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-47: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.37
CMAX 1.26



Table 2-48: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 10 -
Points within Guest et al. 6 60
Points within 2 fold 10 100



Table 2-49: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 8 -
Points within Guest et al. 4 50
Points within 2 fold 8 100



2.3.3 Carbamazepine

Figure 2-65: CYP3A4 DDI. Victim: Carbamazepine. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-66: CYP3A4 DDI. Victim: Carbamazepine. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-67: CYP3A4 DDI. Victim: Carbamazepine. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-68: CYP3A4 DDI. Victim: Carbamazepine. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-50: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.21
CMAX 1.18



Table 2-51: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 6 -
Points within Guest et al. 4 66.67
Points within 2 fold 6 100.00



Table 2-52: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 4 -
Points within Guest et al. 1 25
Points within 2 fold 4 100



2.3.4 Efavirenz

Figure 2-69: CYP3A4 DDI. Victim: Efavirenz. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-70: CYP3A4 DDI. Victim: Efavirenz. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-71: CYP3A4 DDI. Victim: Efavirenz. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-72: CYP3A4 DDI. Victim: Efavirenz. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-53: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.47
CMAX 1.21



Table 2-54: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



Table 2-55: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



2.3.5 Midazolam

Figure 2-73: CYP3A4 DDI. Victim: Midazolam. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-74: CYP3A4 DDI. Victim: Midazolam. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-75: CYP3A4 DDI. Victim: Midazolam. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-76: CYP3A4 DDI. Victim: Midazolam. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-56: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.40
CMAX 1.38



Table 2-57: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 106 -
Points within Guest et al. 78 73.58
Points within 2 fold 90 84.91



Table 2-58: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 67 -
Points within Guest et al. 43 64.18
Points within 2 fold 58 86.57



2.3.6 R-Verapamil

Figure 2-77: CYP3A4 DDI. Victim: R-Verapamil. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-78: CYP3A4 DDI. Victim: R-Verapamil. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-79: CYP3A4 DDI. Victim: R-Verapamil. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-80: CYP3A4 DDI. Victim: R-Verapamil. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-59: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.26
CMAX 1.27



Table 2-60: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



Table 2-61: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



2.3.7 S-Verapamil

Figure 2-81: CYP3A4 DDI. Victim: S-Verapamil. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-82: CYP3A4 DDI. Victim: S-Verapamil. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-83: CYP3A4 DDI. Victim: S-Verapamil. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-84: CYP3A4 DDI. Victim: S-Verapamil. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-62: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.42
CMAX 1.75



Table 2-63: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



Table 2-64: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 1 -
Points within Guest et al. 0 0
Points within 2 fold 1 100



2.3.8 Triazolam

Figure 2-85: CYP3A4 DDI. Victim: Triazolam. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-86: CYP3A4 DDI. Victim: Triazolam. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-87: CYP3A4 DDI. Victim: Triazolam. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-88: CYP3A4 DDI. Victim: Triazolam. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-65: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.42
CMAX 1.16



Table 2-66: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 16 -
Points within Guest et al. 11 68.75
Points within 2 fold 14 87.50



Table 2-67: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 16 -
Points within Guest et al. 13 81.25
Points within 2 fold 16 100.00



2.3.9 Verapamil

Figure 2-89: CYP3A4 DDI. Victim: Verapamil. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-90: CYP3A4 DDI. Victim: Verapamil. Predicted/Observed vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)



Figure 2-91: CYP3A4 DDI. Victim: Verapamil. Predicted vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Figure 2-92: CYP3A4 DDI. Victim: Verapamil. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)



Table 2-68: GMFE for CYP3A4 DDI Ratio

PK parameter GMFE
AUC 1.19
CMAX 1.42



Table 2-69: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

AUC Number Ratio [%]
Points total 8 -
Points within Guest et al. 3 37.50
Points within 2 fold 8 100.00



Table 2-70: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

CMAX Number Ratio [%]
Points total 4 -
Points within Guest et al. 1 25
Points within 2 fold 3 75



3 Concentration-Time Profiles

The following section shows concentration time profiles of the victim drugs of the simulated DDI studies in comparison to observed data (if available).

3.1 Carbamazepine - Alprazolam DDI

Figure 3-1: Furukori 1998



3.2 Carbamazepine - Efavirenz DDI

Figure 3-2: Ji 2008 (Arm 1, Perpetrator: Carbamazepine, Victim: Efavirenz)



3.3 Carbamazepine - Midazolam DDI

Figure 3-3: Datta-Mannan 2024



Figure 3-4: Kanefendt 2023 (Study 1)



Figure 3-5: Kanefendt 2023 (Study 2)



Figure 3-6: Lutz 2018



3.4 Cimetidine - Alfentanil DDI

Figure 3-7: Kienlen 1993



3.5 Cimetidine - Alprazolam DDI

Figure 3-8: Abernethy 1983



Figure 3-9: Pourbaix 1985



3.6 Cimetidine - Carbamazepine DDI

Figure 3-10: Dalton 1985a



3.7 Cimetidine - Midazolam DDI

Figure 3-11: Greenblatt 1986 (midazolam IV)



Figure 3-12: Greenblatt 1986 (midazolam PO)



Figure 3-13: Martinez 1999



Figure 3-14: Fee 1987



Figure 3-15: Salonen 1986



Figure 3-16: Elliott 1984



3.8 Cimetidine - Triazolam DDI

Figure 3-17: Abernethy 1983



Figure 3-18: Friedman 1988



Figure 3-19: Pourbaix 1985



Figure 3-20: Cox 1986



3.9 Cimetidine - Verapamil DDI

Figure 3-21: Abernethy 1985 (verapamil IV)



Figure 3-22: Smith 1984 (verapamil IV)



Figure 3-23: Wing 1985 (verapamil IV)



Figure 3-24: Abernethy 1985 (verapamil PO)



Figure 3-25: Mikus 1990 (verapamil PO), R-verapamil



Figure 3-26: Mikus 1990 (verapamil PO), S-verapamil



Figure 3-27: Smith 1984 (verapamil PO)



Figure 3-28: Wing 1985 (verapamil PO)



3.10 Clarithromycin - Midazolam DDI

Figure 3-29: Gorski 1998 (midazolam IV)



Figure 3-30: Gorski 1998 (midazolam po)



Figure 3-31: Gurley 2006



Figure 3-32: Gurley 2008a



Figure 3-33: Markert 2013



Figure 3-34: Prueksaritanont 2017



Figure 3-35: Quinney 2008 (midazolam IV)



Figure 3-36: Quinney 2008 (midazolam po)



Figure 3-37: van Dyk 2018



Figure 3-38: Yeates 1996



3.11 Clarithromycin - Triazolam DDI

Figure 3-39: Greenblatt 1998a



3.12 Efavirenz - Alfentanil DDI

Figure 3-40: Kharasch 2012 IV



Figure 3-41: Kharasch 2012 PO



3.13 Efavirenz - Carbamazepine DDI

Figure 3-42: Ji 2008 (Arm 2, Perpetrator: Efavirenz, Victim: Carbamazepine)



3.14 Efavirenz - Midazolam DDI

Figure 3-43: Mikus 2017 IV



Figure 3-44: Mikus 2017 PO



Figure 3-45: Katzenmaier 2010



3.15 Erythromycin - Alfentanil DDI

Figure 3-46: Bartkowski 1989



Figure 3-47: Bartkowski 1993



3.16 Erythromycin - Alprazolam DDI

Figure 3-48: Yasui 1996



3.17 Erythromycin - Carbamazepine DDI

Figure 3-49: Barzaghi 1987



Figure 3-50: Wong 1983



Figure 3-51: Miles 1989 (average dose of 357 mg)



Figure 3-52: Miles 1989 (300 mg)



Figure 3-53: Miles 1989 (400 mg)



3.18 Erythromycin - Midazolam DDI

Figure 3-54: Carls 2014



Figure 3-55: Okudaira 2007



Figure 3-56: Olkkola 1993 (midazolam IV)



Figure 3-57: Olkkola 1993 (midazolam po)



Figure 3-58: Swart 2002



Figure 3-59: Zimmermann 1996



3.19 Erythromycin - Triazolam DDI

Figure 3-60: Greenblatt 1998



Figure 3-61: Phillips 1986



3.20 Fluconazole - Alfentanil DDI

Figure 3-62: Palkama 1998



3.21 Fluconazole - Midazolam DDI

Figure 3-63: Ahonen 1997



Figure 3-64: Olkkola 1996 Day 1



Figure 3-65: Olkkola 1996 Day 4



Figure 3-66: Olkkola 1996 Day 6



3.22 Fluconazole - Triazolam DDI

Figure 3-67: Varhe 1996c



3.23 Fluvoxamine - Alprazolam DDI

Figure 3-68: Fleishaker 1994 (Day 1, first dose)



Figure 3-69: Fleishaker 1994 (Day 10)



3.24 Fluvoxamine - Midazolam DDI

Figure 3-70: Kashuba 1998



Figure 3-71: Lam 2003



3.25 Itraconazole - Alprazolam DDI

Figure 3-72: Yasui 1998



3.26 Itraconazole - Midazolam DDI

Figure 3-73: Ahonen 1995



Figure 3-74: Backman 1998



Figure 3-75: Olkkola 1994



Figure 3-76: Olkkola 1996 (day 1 po)



Figure 3-77: Olkkola 1996 (day 4 iv)



Figure 3-78: Olkkola 1996 (day 6 po)



Figure 3-79: Prueksaritanont 2017



Figure 3-80: Templeton 2010



Figure 3-81: Yu 2004 (CYP3A53/3)



3.27 Itraconazole - Triazolam DDI

Figure 3-82: Neuvonen 1996



Figure 3-83: Varhe 1994



3.28 Rifampicin - Alfentanil DDI

Figure 3-84: Kharasch 1997



Figure 3-85: Kharasch 2004 (iv)



Figure 3-86: Kharasch 2004 (po)



Figure 3-87: Kharasch 2011 (iv)



Figure 3-88: Kharasch 2011 (po)



Figure 3-89: Kharasch 2011b (iv during sequential administration of iv unlabeled alfentanil and oral deuterated alfentanil)



Figure 3-90: Kharasch 2011b (iv during simultaneous administration of iv unlabeled alfentanil and oral deuterated alfentanil)



Figure 3-91: Kharasch 2011b (po during sequential administration of iv unlabeled alfentanil and oral deuterated alfentanil)



Figure 3-92: Kharasch 2011b (po during simultaneous administration of iv unlabeled alfentanil and oral deuterated alfentanil)



Figure 3-93: Phimmasone 2001



3.29 Rifampicin - Alprazolam DDI

Figure 3-94: Gashaw 2003 (Day 7)



Figure 3-95: Gashaw 2003 (after washout phase)



Figure 3-96: Schmider 1999



3.30 Rifampicin - Midazolam DDI

Figure 3-97: Backman 1996



Figure 3-98: Backman 1998 (Phase IV and V vs. I)



Figure 3-99: Björkhem-Bergman 2013



Figure 3-100: Chattopadhyay 2018



Figure 3-101: Chung 2006



Figure 3-102: Eap 2004 (7.5 mg)



Figure 3-103: Gorski 2003 (iv)



Figure 3-104: Gorski 2003 (po)



Figure 3-105: Gurley 2006



Figure 3-106: Gurley 2008a



Figure 3-107: Kharasch 1997



Figure 3-108: Kharasch 2004 (iv)



Figure 3-109: Kharasch 2004 (po)



Figure 3-110: Kharasch 2011 (iv)



Figure 3-111: Kharasch 2011 (po)



Figure 3-112: Kim 2018



Figure 3-113: Link 2008 (iv)



Figure 3-114: Link 2008 (po)



Figure 3-115: Lutz 2008



Figure 3-116: Phimmasone 2001



Figure 3-117: Prueksaritanont 2017



Figure 3-118: Reitman 2011



Figure 3-119: Shin 2013



Figure 3-120: Shin 2016



Figure 3-121: Szalat 2007



Figure 3-122: van Dyk 2018



Figure 3-123: Wiesinger 2020



Figure 3-124: Yu 2004 (CYP3A53/3)



3.31 Rifampicin - Triazolam DDI

Figure 3-125: Villikka 1997



3.32 Rifampicin - Verapamil DDI

Figure 3-126: Barbarash 1988 (verapamil IV)



Figure 3-127: Barbarash 1988 (verapamil PO)



3.33 Verapamil - Midazolam DDI

Figure 3-128: Backman 1994



Figure 3-129: Wang 2005 (iv)



Figure 3-130: Wang 2005 (po)



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Erythromycin-Alfentanil-DDI

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Erythromycin-Alprazolam-DDI

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Erythromycin-Carbamazepine-DDI

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Erythromycin-Triazolam-DDI

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Fluconazole-Alfentanil-DDI

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Fluconazole-Midazolam-DDI

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Fluconazole-Triazolam-DDI

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Itraconazole-Midazolam-DDI

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Prueksaritanont 2017 Prueksaritanont T, Tatosian DA, Chu X, Railkar R, Evers R, Chavez-Eng C, Lutz R, Zeng W, Yabut J, Chan GH, Cai X, Latham AH, Hehman J, Stypinski D, Brejda J, Zhou C, Thornton B, Bateman KP, Fraser I,, Stoch SA. Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A. Clin Pharmacol Ther. 2017 Apr;101(4):519-530.

Templeton 2010 Templeton I, Peng CC, Thummel KE, Davis C, Kunze KL, Isoherranen N. Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data. Clin Pharmacol Ther. 2010 Oct;88(4):499-505.

Yu 2004 Yu KS, Cho JY, Jang IJ, Hong KS, Chung JY, Kim JR, Lim HS, Oh DS, Yi SY, Liu KH, Shin JG, Shin SG. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther. 2004 Aug;76(2):104-12.

Itraconazole-Triazolam-DDI

Neuvonen 1996 Neuvonen PJ, Varhe A, Olkkola KT. The effect of ingestion time interval on the interaction between itraconazole and triazolam. Clin Pharmacol Ther. 1996 Sep;60(3):326-31.

Varhe 1994 Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994 Dec;56(6 Pt 1):601-7.

Rifampicin-Alfentanil-DDI

Kharasch 1997 Kharasch ED, Russell M, Mautz D, Thummel KE, Kunze KL, Bowdle A, Cox K. The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology. 1997 Jul;87(1):36-50.

Kharasch 2004 Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004 Nov;76(5):452-66.

Kharasch 2011 Kharasch ED, Francis A, London A, Frey K, Kim T, Blood J. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther. 2011 Jul;90(1):100-8.

Kharasch 2011b Kharasch ED, Vangveravong S, Buck N, London A, Kim T, Blood J, Mach RH. Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil. Clin Pharmacol Ther. 2011 Apr;89(4):562-70.

Phimmasone 2001 Phimmasone S, Kharasch ED. A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther. 2001 Dec;70(6):505-17.

Rifampicin-Alprazolam-DDI

Gashaw 2003 Gashaw, I., Kirchheiner, J., Goldammer, M., Bauer, S., Seidemann, J., Zoller, K., ... & Brockmöller, J. (2003). Cytochrome p450 3A4 messenger ribonucleic acid induction by rifampin in human peripheral blood mononuclear cells: correlation with alprazolam pharmacokinetics. Clinical Pharmacology & Therapeutics, 74(5), 448-457.

Schmider 1999 Schmider, J., Brockmöller, J., Arold, G., Bauer, S., & Roots, I. (1999). Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics, 9(6), 725-734.

Rifampicin-Midazolam-DDI

Backman 1996 Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther. 1996 Jan;59(1):7-13.

Backman 1998 Backman JT, Kivistö KT, Olkkola KT, Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol. 1998 Mar;54(1):53-8.

Björkhem-Bergman 2013 Björkhem-Bergman L, Bäckström T, Nylén H, Rönquist-Nii Y, Bredberg E, Andersson TB, Bertilsson L, Diczfalusy U. Comparison of endogenous 4β-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013 Aug;41(8):1488-93.

Chattopadhyay 2018 Chattopadhyay N, Kanacher T, Casjens M, Frechen S, Ligges S, Zimmermann T, Rottmann A, Ploeger B, Höchel J, Schultze-Mosgau MH. CYP3A4-mediated effects of rifampicin on the pharmacokinetics of vilaprisan and its UGT1A1-mediated effects on bilirubin glucuronidation in humans. Br J Clin Pharmacol. 2018 Dec;84(12):2857-2866.

Chung 2006 Chung E, Nafziger AN, Kazierad DJ, Bertino JS Jr. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther. 2006 Apr;79(4):350-61.

Eap 2004 Eap CB, Buclin T, Cucchia G, Zullino D, Hustert E, Bleiber G, Golay KP, Aubert AC, Baumann P, Telenti A, Kerb R. Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity. Eur J Clin Pharmacol. 2004 Jun;60(4):237-46.

Gorski 2003 Gorski JC, Vannaprasaht S, Hamman MA, Ambrosius WT, Bruce MA, Haehner-Daniels B, Hall SD. The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther. 2003 Sep;74(3):275-87.

Gurley 2006 Gurley B, Hubbard MA, Williams DK, Thaden J, Tong Y, Gentry WB, Breen P, Carrier DJ, Cheboyina S. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol. 2006 Feb;46(2):201-13.

Gurley 2008a Gurley BJ, Swain A, Hubbard MA, Hartsfield F, Thaden J, Williams DK, Gentry WB, Tong Y. Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo. Clin Pharmacol Ther. 2008 Jan;83(1):61-9.

Kharasch 1997 Kharasch ED, Russell M, Mautz D, Thummel KE, Kunze KL, Bowdle A, Cox K. The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology. 1997 Jul;87(1):36-50.

Kharasch 2004 Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004 Nov;76(5):452-66.

Kharasch 2011 Kharasch ED, Francis A, London A, Frey K, Kim T, Blood J. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther. 2011 Jul;90(1):100-8.

Kim 2018 Kim B, Lee J, Shin KH, Lee S, Yu KS, Jang IJ, Cho JY. Identification of ω- or (ω-1)-Hydroxylated Medium-Chain Acylcarnitines as Novel Urinary Biomarkers for CYP3A Activity. Clin Pharmacol Ther. 2018 May;103(5):879-887.

Link 2008 Link B, Haschke M, Grignaschi N, Bodmer M, Aschmann YZ, Wenk M, Krähenbühl S. Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping. Br J Clin Pharmacol. 2008 Oct;66(4):473-84.

Lutz 2018 Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin. Clin Pharmacol Ther. 2018 Dec;104(6):1182-1190.

Phimmasone 2001 Phimmasone S, Kharasch ED. A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther. 2001 Dec;70(6):505-17.

Prueksaritanont 2017 Prueksaritanont T, Tatosian DA, Chu X, Railkar R, Evers R, Chavez-Eng C, Lutz R, Zeng W, Yabut J, Chan GH, Cai X, Latham AH, Hehman J, Stypinski D, Brejda J, Zhou C, Thornton B, Bateman KP, Fraser I, Stoch SA. Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A. Clin Pharmacol Ther. 2017 Apr;101(4):519-530.

Reitman 2011 Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone JA, Ding Y, Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A. Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design. Clin Pharmacol Ther. 2011 Feb;89(2):234-42.

Shin 2013 Shin KH, Choi MH, Lim KS, Yu KS, Jang IJ, Cho JY. Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. Clin Pharmacol Ther. 2013 Nov;94(5):601-9.

Shin 2016 Shin KH, Ahn LY, Choi MH, Moon JY, Lee J, Jang IJ, Yu KS, Cho JY. Urinary 6β-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach. AAPS J. 2016 Sep;18(5):1254-1261.

Szalat 2007 Szalat A, Gershkovich P, Ben-Ari A, Shaish A, Liberman Y, Boutboul E, Gotkine M, Hoffman A, Harats D, Leitersdorf E, Meiner V. Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment. Biochim Biophys Acta. 2007 Jul;1771(7):839-44.

van Dyk 2018 van Dyk M, Marshall JC, Sorich MJ, Wood LS, Rowland A. Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries. Eur J Clin Pharmacol. 2018 Jul;74(7):913-920.

Wiesinger 2020 Wiesinger H, Klein S, Rottmann A, Nowotn B, Riecke K, Gashaw I, Brudny-Klöppel M, Fricke R, Höchel J, Friedrich C. The effects of weak and strong CYP3A induction by rifampicin on the pharmacokinetics of five progestins and ethinylestradiol compared to midazolam. Clin Pharmacol Ther. 2020 Apr 10.

Yu 2004 Yu KS, Cho JY, Jang IJ, Hong KS, Chung JY, Kim JR, Lim HS, Oh DS, Yi SY, Liu KH, Shin JG, Shin SG. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther. 2004 Aug;76(2):104-12.

Rifampicin-Triazolam-DDI

Villikka 1997 Villikka K, Kivistö KT, Backman JT, Olkkola KT, & Neuvonen PJ. Triazolam is ineffective in patients taking rifampin. Clin Pharmacol Ther. 1997 Jan;61(1):8-14.

Rifampicin-Verapamil-DDI

Barbarash 1988 Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total reduction in verapamil bioavailability by rifampin. Electrocardiographic correlates. Chest. 1988 Nov;94(5):954-9.

Verapamil-Midazolam-DDI

Backman 1994 Backman JT, Olkkola KT, Aranko K, Himberg JJ, Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol. 1994 Mar;37(3):221-5.

Wang 2005 Wang Y, Jin Y, Hilligoss JK, Ho H, Hamman MA, Hu Z, Gorski JD, Hall SD. Effect of CYP3A5 genotype on the extent of CYP3A inhibition by verapamil. Clin Pharmacol Ther. 2005; 77(2):P3.

5 Appendix

5.1 Open Systems Pharmacology Suite (OSPS) Introduction

Open Systems Pharmacology Suite (OSP suite) is a tool for PBPK modeling and simulation of drugs in laboratory animals and humans. PK-Sim® and MoBi® are part of the OSP suite [1]. PK-Sim® is based on a generic PBPK-model with 18 organs and tissues. One of the main assumptions is that all compartments are well-stirred. Represented organs/tissues include arterial and venous blood, adipose tissue (separable adipose, excluding yellow marrow), brain, lung, bone (including yellow marrow), gonads, heart, kidneys, large intestine, liver, muscle, portal vein, pancreas, skin, small intestine, spleen and stomach, as shown in Figure Appendix-1.

Each organ consists of four sub-compartments namely the plasma, blood cells (which together build the vascular space), interstitial space, and cellular space. Distribution between the plasma and blood cells as well as between the interstitial and cellular compartments can be permeability-limited. In the brain, the permeation barrier is located between the vascular and the interstitial space. PK-Sim® estimates model parameters (intestinal permeability [2] organ partition coefficients (tissue-to-plasma partition coefficients) [3,4], and permeabilities) from physico-chemical properties of compounds (molecular weight, pKa, acid/base properties) and the composition of each tissue compartment (lipids, water and proteins). Partition coefficients can be calculated using a variety of methods available in PK-Sim®, for example the internal PK-Sim® method [3,4] or that of Rodgers and Rowland [5-7].

Physiological databases included in the software incorporate the dependencies of organ composition, organ weights, organ blood flows and gastrointestinal parameters (gastrointestinal length, radius of each section, intestinal surface area, gastrointestinal transit times, and pH in different intestinal segments [2]), with the user-defined body weight and height and ethnicity of the individual [8]. Thereby, PK Sim® allows generating realistic virtual populations. For a detailed description of the PBPK model structure implemented in PK Sim®, see Willmann et al. [2,4,8,9] or the OSP Suite homepage (https://docs.open-systems-pharmacology.org/mechanistic-modeling-of-pharmacokinetics-and-dynamics/modeling-concepts).

generic PBPK model

Figure Appendix-1: Structure of the Whole Body PBPK Model integrated in PK-Sim®

References for OSPS introduction

[1] www.open-systems-pharmacology.org

[2] Willmann S, Schmitt W, Keldenich J, Lippert J, Dressman JB. A physiological model for the estimation of the fraction dose absorbed in humans.J Med Chem. 2004 Jul 29;47(16):4022-31.

[3] Haerter MW, K.J., Schmitt W, Estimation of physicochemical and ADME parameters. , in Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materials, H.W. Nicolaou KC HR, Editor. 2002, Wiley VCH Verlag GmbH: Weinheim, Germany. p. 743-60.

[4] Willmann S, Lippert J, Schmitt W. From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools. Expert Opin Drug Metab Toxicol. 2005 Jun;1(1):159-68.

[5] Rodgers, T, D. Leahy, and M. Rowland. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005 Jun;94(6):1259-76.

[6] Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006 Jun;95(6):1238-57.

[7] Rodgers T, Rowland M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharm Res. 2007 May;24(5):918-33.

[8] Willmann S, Höhn K, Edginton A, Sevestre M, Solodenko J, Weiss W, Lippert J, Schmitt W. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007 Jun;34(3):401-31.

[9] Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 2003.1(4):121-24.

5.2 Mathematical Implementation of Drug-Drug Interactions

DDI modeling: Competitive inhibition

A detailed representation of the mathematical implementation of competitive enzyme inhibition can be found in the OSP manual (https://docs.open-systems-pharmacology.org/working-with-pk-sim/pk-sim-documentation/pk-sim-compounds-defining-inhibition-induction-processes#competitive-inhibition-simple-setting-with-one-inhibitor).

DDI modeling: Mechanism-based inhibition

A detailed representation of the mathematical implementation of mechanism-based enzyme inhibition can be found in the OSP manual (https://docs.open-systems-pharmacology.org/working-with-pk-sim/pk-sim-documentation/pk-sim-compounds-defining-inhibition-induction-processes#irreversible-inhibition).

DDI modeling: Induction

A detailed representation of the mathematical implementation of enzyme induction can be found in the OSP manual (https://docs.open-systems-pharmacology.org/working-with-pk-sim/pk-sim-documentation/pk-sim-compounds-defining-inhibition-induction-processes#enzyme-induction).

5.3 Automatic (re)-qualification workflow

Open Systems Pharmacology (https://www.open-systems-pharmacology.org/) provides a dynamic landscape of model repositories and a database of observed clinical data. Additionally, a technical framework to assess confidence of a specific intended use has been developed (qualification runner and reporting engine). This framework allows for an automatic (re)-qualification workflow of the OSP suite, comprising the following steps Figure Appendix-2:

  • PBPK model development and verification with observed data,

  • Qualification plan generation,

  • Qualification plan execution,

  • Qualification report generation.

OSP qualification workflow

Figure Appendix-2: OSP suite automatic (re)-qualification workflow

In a first step, the respective qualification scenario is saved in a special qualification repository on OSP GitHub (https://github.com/Open-Systems-Pharmacology/). This qualification scenario repository contains a detailed qualification plan that links and combines respective models and data to address the use case that shall be qualified. Therefore, the qualification plan consists of:

  • PK-Sim project files,
  • Additional model building steps (if applicable),
  • Description of potential cross-dependencies between PK-Sim project files (if applicable),
  • Observed data (needed for model development and verification),
  • Qualification scenario description text modules
  • Detailed report settings to describe the generation of charts and qualification measures.

PK-Sim projects, observed data sets, and qualification scenario text modules are deposited in distinct repositories and are referenced by the qualification plan (Figure Appendix-3).

OSP qualification workflow detail

Figure Appendix-3: Qualification scenario repository landscape on GitHub

In a second step the qualification runner (https://github.com/Open-Systems-Pharmacology/QualificationRunner) processes the qualification plan, i.e. all project parts are exported and prepared for the reporting engine (https://github.com/Open-Systems-Pharmacology/Reporting-Engine). The reporting engine provides a validated environment (implemented in R) for model execution and finally generates the qualification report. This report contains the evaluation of the individual PBPK models with observed data (i.e. standard goodness of fit plots, visual predictive checks) and a comprehensive qualification of the specific use case assessing the predictive performance of the OSP suite by means of a predefined set of qualification measures and charts.

The automated execution of the described workflow can be triggered to assess re-qualification in case new data, changes in model structure or parameterization, or new OSP suite releases arise.

Other Drug-Drug Interaction (DDI) qualification reports:

View all Drug-Drug Interaction (DDI) →

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