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Building and Evaluation of a PBPK Model for Verapamil in Adults

Version 2.2-OSP12.3
based on Model Snapshot and Evaluation Plan https://github.com/Open-Systems-Pharmacology/Verapamil-Model/releases/tag/v2.2
OSP Version 12.3
Qualification Framework Version 3.6

This evaluation report and the corresponding PK-Sim project file are filed at:

https://github.com/Open-Systems-Pharmacology/OSP-PBPK-Model-Library/

Table of Contents

1 Introduction

Verapamil is used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia.

Verapamil is administered as a 1:1 racemat of R- and S-verapamil which are metabolized mainly by CYP3A4 to S- and R-norverapamil. All four entities are mechanism-based inactivators of CYP3A4 and non-competitive inhibitors of P-gp.

The presented verapamil model was established using observed concentration-time profiles of more than 45 clinical studies with doses from 0.1 mg to 250 mg in different verapamil dosing schedules including multiple doses and different routes of administration (intravenous, single and multiple oral administration). It includes enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific P-gp transport, and passive glomerular filtration The model building and application has been published by Hanke et al. 2020 (Hanke 2020).

The herein presented model building and evaluation report evaluates the performance of the PBPK model for verapamil in (healthy) adults.

2 Methods

2.1 Modeling Strategy

The general concept of building a PBPK model has previously been described by e.g. Kuepfer et al. (Kuepfer 2016). The relevant anthropometric (height, weight) and physiological information (e.g. blood flows, organ volumes, binding protein concentrations, hematocrit, cardiac output) in adults was gathered from the literature and has been previously published (Schlender 2016). This information was incorporated into PK-Sim® and was used as default values for the simulations in adults.

Variability of plasma proteins and CYP enzymes are integrated into PK-Sim® and described in the publicly available PK-Sim® Ontogeny Database Version 7.3 (PK-Sim Ontogeny Database Version 7.3, Schlender 2016) or otherwise referenced for the specific process.

First, a base mean model was built and adjusted to clinical data including single and multiple dose studies with intravenous (only single dose) and oral applications of verapamil to find an appropriate structure to describe the pharmacokinetics in plasma. The mean PBPK model was developed using a typical European individual adjusted to the demography of the respective study population.

Unknown parameters (see below) were identified using the Parameter Identification module provided in PK-Sim®. Structural model selection was mainly guided by visual inspection of the resulting description of data and biological plausibility.

Details about input data (physicochemical, in vitro and clinical) can be found in Section 2.2.

Details about the structural model and its parameters can be found in Section 2.3.

2.2 Data

In vitro / physico-chemical Data

A literature search was performed to collect available information on physiochemical properties of R- and S-verapamil and R- and S-norverapamil. The obtained information from literature is summarized in the tables below.

R-verapamil

Parameter Unit Value Source Description
MW g/mol 454.611 Wishart 2006 Molecular weight
pKa (base) - 8.75 Hasegawa 1984 Acid dissociation constant
Solubility (pH 6.54) g/L 46.0 Vogelpoel 2004 Water solubility
logP 3.79 Hansch 1995 Partition coefficient between octanol and water
fu % 5.1 Sanaee 2011 Fraction unbound in plasma
CYP3A4 Km -> Norvera µmol/L 19.59 Wang 2013 CYP3A4 Michaelis-Menten constant for norverapamil formation
CYP3A4 Km -> D617 µmol/L 35.34 Wang 2013 CYP3A4 Michaelis-Menten constant for D617 formation
P-gp Km µmol/L 1.01 Shirasaka 2008 Pgp Michaelis-Menten constant
CYP3A4 MBI KI µmol/L 27.63 Wang 2013 Conc. for half-maximal inactivation
CYP3A4 MBI kinact 1/min 0.038 Wang 2013 Maximum inactivation rate
Pgp non-competitive Ki µmol/L 0.31 Döppenschmitt 1999 Conc. for half-maximal inactivation

S-verapamil

Parameter Unit Value Source Description
MW g/mol 454.611 Wishart 2006 Molecular weight
pKa (base) - 8.75 Hasegawa 1984 Acid dissociation constant
Solubility (pH 6.54) g/L 46.0 Vogelpoel 2004 Water solubility
logP 3.79 Hansch 1995 Partition coefficient between octanol and water
fu % 11 Sanaee 2011 Fraction unbound in plasma
CYP3A4 Km -> Norvera µmol/L 9.72 Wang 2013 CYP3A4 Michaelis-Menten constant for norverapamil formation
CYP3A4 Km -> D617 µmol/L 23.64 Wang 2013 CYP3A4 Michaelis-Menten constant for D617 formation
P-gp Km µmol/L 1.01 Shirasaka 2008 Pgp Michaelis-Menten constant
CYP3A4 MBI KI µmol/L 3.85 Wang 2013 Conc. for half-maximal inactivation
CYP3A4 MBI kinact 1/min 0.034 Wang 2013 Maximum inactivation rate
Pgp non-competitive Ki µmol/L 0.31 Döppenschmitt 1999 (#5-references) Conc. for half-maximal inactivation

R-norverapamil

Parameter Unit Value Source Description
MW g/mol 440.584 Wishart 2006 Molecular weight
pKa (base) - 8.6 - 8.9 Sigma-Aldrich 2013 Acid dissociation constant
fu % 5.1 assumed (from parent) Fraction unbound in plasma
CYP3A4 Km -> D620 µmol/L 144 Tracy 1999 CYP3A4 Michaelis-Menten constant for norverapamil degradation
P-gp Km µmol/L 1.01 assumed (from parent) Pgp Michaelis-Menten constant
CYP3A4 MBI KI µmol/L 6.1 Wang 2013 Conc. for half-maximal inactivation
CYP3A4 MBI kinact 1/min 0.048 Wang 2013 Maximum inactivation rate
Pgp non-competitive Ki µmol/L 0.30 Pauli-Magnus 2000 Conc. for half-maximal inactivation

S-norverapamil

Parameter Unit Value Source Description
MW g/mol 440.584 Wishart 2006 Molecular weight
pKa (base) - 8.6 - 8.9 Sigma-Aldrich 2013 Acid dissociation constant
fu % 11 assumed (from parent) Fraction unbound in plasma
CYP3A4 Km -> D620 µmol/L 36 Tracy 1999 CYP3A4 Michaelis-Menten constant for norverapamil degradation
P-gp Km µmol/L 1.01 assumed (from parent) Pgp Michaelis-Menten constant
CYP3A4 MBI KI µmol/L 2.90 Wang 2013 Conc. for half-maximal inactivation
CYP3A4 MBI kinact 1/min 0.080 Wang 2013 Maximum inactivation rate
Pgp non-competitive Ki µmol/L 0.30 Pauli-Magnus 2000 Conc. for half-maximal inactivation

Individual

Parameter Unit Value Source Description
EHC continuous fraction 1 Assumption EHC continuous fraction

Clinical Data

A literature search was performed to collect available clinical data on verapamil in healthy adults.

Model Building and parameterizing of CYP3A4 interaction

The following studies were used for model building and parameterization of CYP3A4 interaction: If not stated otherwise, the drug was given as a 1:1 racemat of S- and R-verapamil.

Publication Arm / Treatment / Information used for model building
Eichelbaum 1984 Healthy subjects receiving single intravenous doses of 5, 25 and 50 mg of R-verapamil and 5, 7.5 and 10 mg of S-verapamil
Streit 2005 Healthy subjects receiving single intravenous doses of 5 mg
Barbarash 1988 Healthy subjects receiving single intravenous doses of 10 mg
Abernethy 1993 Healthy subjects receiving single intravenous doses of 20 mg
Maeda 2011 Healthy subjects receiving single oral doses of 0.1, 3 and 16 mg
Blume 1989 Healthy subjects receiving single oral doses of 80 mg
Ratiopharm 1988 Healthy subjects receiving single oral doses of 80 mg
Johnson 2001 Healthy subjects receiving multiple oral doses of 80 mg TID.
Härtter 2012 Healthy subjects receiving single oral doses of 120 mg and multiple oral doses of 120 mg BID
Hla 1987 Healthy subjects receiving multiple oral doses of 120 mg BID

Model verification

The following studies were used for model verification:

Publication Arm / Treatment / Information used for model building
Mooy 1985 Healthy subjects receiving single intravenous doses of 3 mg and single oral doses of 80 mg
Johnston 1981 Healthy subjects receiving single intravenous doses of 0.1 mg/kg and single oral doses of 120 mg
Abernethy 1985 Healthy subjects receiving single intravenous doses of 10 mg and single oral doses of 120 mg
Barbarash 1988 Healthy subjects receiving single oral doses of 120 mg
Wing 1985 Healthy subjects receiving single intravenous doses 10mg and single oral doses of 80 mg
McAllister 1982 Healthy subjects receiving single intravenous doses of 10 mg
Smith 1984 Healthy subjects receiving single intravenous doses of 10 mg and single oral doses of 120 mg
Freedman 1981 Healthy subjects receiving single intravenous doses of 13.1 mg
Vogelsang 1984 Healthy subjects receiving single oral doses of 250mg R-verapamil
Blume 1983 Healthy subjects receiving single oral doses of 40 mg
Blume 1990 Healthy subjects receiving single oral doses of 40 mg
John 1992 Healthy subjects receiving single oral doses of 40 mg
Sawicki 2002 Healthy subjects receiving single oral doses of 40 mg
Choi 2008 Healthy subjects receiving single oral doses of 60 mg
Wing 1985 Healthy subjects receiving single oral doses of 80 mg
Maeda 2011 Healthy subjects receiving single oral doses of 80 mg
Ratiopharm 1989 Healthy subjects receiving single oral doses of 80 mg
Boehringer 2018 Healthy subjects receiving single oral doses of 120 mg
Blume 1987 Healthy subjects receiving single oral doses of 120 mg
Johnston 1981 Healthy subjects receiving single oral doses of 120 mg
Mikus 1990 Healthy subjects receiving single oral doses of 160 mg
van Haarst 2009 Healthy subjects receiving multiple oral doses of 180 mg BID
Blume 1994 Healthy subjects receiving single oral doses of 240 mg QD
Joergenson 1988 Healthy subjects receiving multiple oral doses of 120 mg BID
Shand 1981 Healthy subjects receiving multiple oral doses of 120 mg TID
Karim 1995 Healthy subjects receiving single oral doses of 240 mg

2.3 Model Parameters and Assumptions

Absorption

Verapamil is transported by P-gp. The model includes non-stereospecific P-gp transport.

Distribution

After testing the available organ-plasma partition coefficient and cell permeability calculation methods built in PK-Sim, observed clinical data was best described by choosing the partition coefficient calculation by Rodgers and Rowland and cellular permeability calculation by PK-Sim Standard.

Metabolism, Elimination and Inhibition

Verapamil is metabolized by CYP3A4 and transported by P-gp. The model includes enantioselective metabolism by CYP3A4, non-stereospecific P-gp transport. Additionally passive glomerular filtration was integrated. For biliary excretion, an EHC continuous fraction of 1 was assumed.

Mechanism-based inactivation of CYP3A4 and non-competitive inhibition of P-gp by all four entities (S-verapamil, R-verapamil, S-norverapamil and R-norverapamil) was taken into account. The CYP3A4 MBI KI and kinact values were taken from literature, the KI values for P-gp inhibition were optimized.

Automated Parameter Identification

The parameter identification tool in PK-Sim has been used to estimate selected model parameters by adjusting to PK data of the clinical studies that were used in the model building process.

The result of the final parameter identification is shown in the tables below:

R-verapamil

Model Parameter Optimized Value Unit
logP 2.84
CYP3A4 kcat -> Norvera 34.94 1/min
CYP3A4 kcat -> D617 43.98 1/min
P-gp kcat 12.60 1/min
Pgp non-competitive Ki 0.038 µmol/L
Cellular permeability 9.94E-02 cm/min
Intestinal permeability 3.54E-06 cm/min
SR tablet Weibull time 155.24 min
SR tablet Weibull shape 2.37

S-verapamil

Model Parameter Optimized Value Unit
logP 2.84
CYP3A4 kcat -> Norvera 26.17 1/min
CYP3A4 kcat -> D617 56.42 1/min
P-gp kcat 12.60 1/min
Pgp non-competitive Ki 0.038 µmol/L
Cellular permeability 9.94E-02 cm/min
Intestinal permeability 3.54E-06 cm/min
SR tablet Weibull time 155.24 min
SR tablet Weibull shape 2.37

R-norverapamil

Model Parameter Optimized Value Unit
logP 2.84
CYP3A4 kcat -> D620 145.64 1/min
P-gp kcat 3.39 1/min
Pgp non-competitive Ki 0.038 µmol/L
Cellular permeability 9.94E-02 cm/min
Intestinal permeability 3.54E-06 cm/min

S-norverapamil

Model Parameter Optimized Value Unit
logP 2.84
CYP3A4 kcat -> D620 41.10 1/min
P-gp kcat 3.39 1/min
Pgp non-competitive Ki 0.038 µmol/L
Cellular permeability 9.94E-02 cm/min
Intestinal permeability 3.54E-06 cm/min

Individual

Model Parameter Optimized Value Unit
EHC continuous fraction 1

3 Results and Discussion

The PBPK model for verapamil was developed and evaluated using publically available, clinical pharmacokinetic data from studies listed in Section 2.2.

The next sections show:

  1. the final model parameters for the building blocks: Section 3.1.
  2. the overall goodness of fit: Section 3.2.
  3. simulated vs. observed concentration-time profiles for the clinical studies used for model building and for model verification: Section 3.3.

3.1 Final input parameters

The compound parameter values of the final PBPK model are illustrated below.

Compound: R-Verapamil

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 46 mg/ml Measurement True
Reference pH 6.54 Measurement True
Lipophilicity 2.8407448658 Log Units Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 logP True
Fraction unbound (plasma, reference value) 5.1 % Publication-In Vivo Measurement True
Permeability 0.0994098912 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Specific intestinal permeability (transcellular) 3.5447164381E-06 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Is small molecule Yes
Molecular weight 454.611 g/mol
Plasma protein binding partner Unknown

Calculation methods

Name Value
Partition coefficients Rodgers and Rowland
Cellular permeabilities PK-Sim Standard

Processes

Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1
Transport Protein: P-gp-Paper

Molecule: P-gp

Parameters
Name Value Value Origin
In vitro Vmax/transporter 0.00057724 pmol/min/pmol transporter
Km 1.01 µmol/l
kcat 12.5970868779 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: P-gp-Non-competitive

Molecule: P-gp

Parameters
Name Value Value Origin
Ki 0.0383697779 µmol/l Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: CYP3A4-MBI

Molecule: CYP3A4

Parameters
Name Value Value Origin
kinact 0.038 1/min
K_kinact_half 27.63 µmol/l
Metabolizing Enzyme: CYP3A4-Norverapamil

Molecule: CYP3A4

Metabolite: R-Norverapamil

Parameters
Name Value Value Origin
In vitro Vmax for liver microsomes 1.27 nmol/min/mg mic. protein
Km 19.59 µmol/l
kcat 34.9352466212 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Metabolizing Enzyme: CYP3A4-D617

Molecule: CYP3A4

Parameters
Name Value Value Origin
In vitro Vmax for liver microsomes 1.17 nmol/min/mg mic. protein
Km 35.34 µmol/l
kcat 43.9812289146 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23

Compound: S-Verapamil

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 46 mg/ml Measurement True
Reference pH 6.54 Measurement True
Lipophilicity 2.8407448658 Log Units Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 logP True
Fraction unbound (plasma, reference value) 11 % Publication-In Vivo Measurement True
Permeability 0.0994098912 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Specific intestinal permeability (transcellular) 3.5447164381E-06 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Is small molecule Yes
Molecular weight 454.611 g/mol
Plasma protein binding partner Unknown

Calculation methods

Name Value
Partition coefficients Rodgers and Rowland
Cellular permeabilities PK-Sim Standard

Processes

Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1
Transport Protein: P-gp-Paper

Molecule: P-gp

Parameters
Name Value Value Origin
In vitro Vmax/transporter 0.00057724 pmol/min/pmol transporter
Km 1.01 µmol/l
kcat 12.5970868779 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: P-gp-Non-competitive

Molecule: P-gp

Parameters
Name Value Value Origin
Ki 0.0383697779 µmol/l Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: CYP3A4-MBI

Molecule: CYP3A4

Parameters
Name Value Value Origin
kinact 0.034 1/min
K_kinact_half 3.85 µmol/l
Metabolizing Enzyme: CYP3A4-Norverapamil

Molecule: CYP3A4

Metabolite: S-Norverapamil

Parameters
Name Value Value Origin
In vitro Vmax for liver microsomes 1.02 nmol/min/mg mic. protein
Km 9.72 µmol/l
kcat 26.1743386639 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Metabolizing Enzyme: CYP3A4-D617

Molecule: CYP3A4

Parameters
Name Value Value Origin
In vitro Vmax for liver microsomes 0.86 nmol/min/mg mic. protein
Km 23.64 µmol/l
kcat 56.4245798193 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23

Compound: R-Norverapamil

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 46 mg/ml Measurement True
Reference pH 6.54 Measurement True
Lipophilicity 2.8407448658 Log Units Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 logP True
Fraction unbound (plasma, reference value) 5.1 % Other-Assumption Measurement True
Permeability 0.0994098912 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Specific intestinal permeability (transcellular) 3.5447164381E-06 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Is small molecule Yes
Molecular weight 440.584 g/mol
Plasma protein binding partner Unknown

Calculation methods

Name Value
Partition coefficients Rodgers and Rowland
Cellular permeabilities PK-Sim Standard

Processes

Metabolizing Enzyme: CYP3A4-D620

Molecule: CYP3A4

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 9 pmol/min/pmol rec. enzyme
Km 144 µmol/l
kcat 145.6385399671 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1
Transport Protein: P-gp-Paper

Molecule: P-gp

Parameters
Name Value Value Origin
In vitro Vmax/transporter 0.00057724 pmol/min/pmol transporter
Km 1.01 µmol/l
kcat 3.3916609583 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: P-gp-Non-competitive

Molecule: P-gp

Parameters
Name Value Value Origin
Ki 0.0383697779 µmol/l Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: CYP3A4-MBI

Molecule: CYP3A4

Parameters
Name Value Value Origin
kinact 0.048 1/min
K_kinact_half 6.1 µmol/l

Compound: S-Norverapamil

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 46 mg/ml Measurement True
Reference pH 6.54 Measurement True
Lipophilicity 2.8407448658 Log Units Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 logP True
Fraction unbound (plasma, reference value) 11 % Other-Assumption Measurement True
Permeability 0.0994098912 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Specific intestinal permeability (transcellular) 3.5447164381E-06 cm/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23 Fitted True
Is small molecule Yes
Molecular weight 440.584 g/mol
Plasma protein binding partner Unknown

Calculation methods

Name Value
Partition coefficients Rodgers and Rowland
Cellular permeabilities PK-Sim Standard

Processes

Metabolizing Enzyme: CYP3A4-D620

Molecule: CYP3A4

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 6.5 pmol/min/pmol rec. enzyme
Km 36 µmol/l
kcat 41.0994047535 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1
Transport Protein: P-gp-Paper

Molecule: P-gp

Parameters
Name Value Value Origin
In vitro Vmax/transporter 0.00057724 pmol/min/pmol transporter
Km 1.01 µmol/l
kcat 3.3916609583 1/min Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: P-gp-Non-competitive

Molecule: P-gp

Parameters
Name Value Value Origin
Ki 0.0383697779 µmol/l Parameter Identification-Parameter Identification-Value updated from '30b - final' on 2019-12-30 13:23
Inhibition: CYP3A4-MBI

Molecule: CYP3A4

Parameters
Name Value Value Origin
kinact 0.08 1/min
K_kinact_half 2.9 µmol/l

Formulation: Solution

Type: Dissolved

Formulation: Retard Tablet Verapamil (Knoll)

Type: Weibull

Parameters

Name Value Value Origin
Dissolution time (50% dissolved) 155.2445399403 min Parameter Identification-Parameter Identification-Value updated from '240 mg retard (Isoptin RR) QD vs Verabeta 240 RR' on 2019-12-31 11:13
Lag time 0 min
Dissolution shape 2.3662989419 Parameter Identification-Parameter Identification-Value updated from '240 mg retard (Isoptin RR) QD vs Verabeta 240 RR' on 2019-12-31 11:13
Use as suspension Yes

3.2 Diagnostics Plots

Below you find the goodness-of-fit visual diagnostic plots for the PBPK model performance of all data used presented in Section 2.2.

The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time.

Table 3-1: GMFE for Goodness of fit plot for concentration in plasma

Group GMFE
Intravenous administration - norverapamil 1.66
Intravenous administration - R-verapamil 1.25
Intravenous administration - S-verapamil 1.31
Intravenous administration - verapamil 1.44
Oral administration - norverapamil 1.29
Oral administration - R-norverapamil 1.14
Oral administration - R-verapamil 1.33
Oral administration - S-norverapamil 1.16
Oral administration - S-verapamil 1.31
Oral administration - verapamil 1.42
All 1.35



Figure 3-1: Goodness of fit plot for concentration in plasma



Figure 3-2: Goodness of fit plot for concentration in plasma



3.3 Concentration-Time Profiles

Simulated versus observed concentration-time profiles of all data listed in Section 2.2 are presented below.

Figure 3-3: Time Profile Analysis



Figure 3-4: Time Profile Analysis



Figure 3-5: Time Profile Analysis



Figure 3-6: Time Profile Analysis



Figure 3-7: Time Profile Analysis



Figure 3-8: Time Profile Analysis



Figure 3-9: Time Profile Analysis



Figure 3-10: Time Profile Analysis



Figure 3-11: Time Profile Analysis



Figure 3-12: Time Profile Analysis



Figure 3-13: Time Profile Analysis



Figure 3-14: Time Profile Analysis



Figure 3-15: Time Profile Analysis



Figure 3-16: Time Profile Analysis



Figure 3-17: Time Profile Analysis



Figure 3-18: Time Profile Analysis



Figure 3-19: Time Profile Analysis



Figure 3-20: Time Profile Analysis



Figure 3-21: Time Profile Analysis



Figure 3-22: Time Profile Analysis



Figure 3-23: Time Profile Analysis



Figure 3-24: Time Profile Analysis



Figure 3-25: Time Profile Analysis



Figure 3-26: Time Profile Analysis



Figure 3-27: Time Profile Analysis



Figure 3-28: Time Profile Analysis



Figure 3-29: Time Profile Analysis



Figure 3-30: Time Profile Analysis



Figure 3-31: Time Profile Analysis



Figure 3-32: Time Profile Analysis



Figure 3-33: Time Profile Analysis



Figure 3-34: Time Profile Analysis



Figure 3-35: Time Profile Analysis



Figure 3-36: Time Profile Analysis



Figure 3-37: Time Profile Analysis



Figure 3-38: Time Profile Analysis



Figure 3-39: Time Profile Analysis



Figure 3-40: Time Profile Analysis



Figure 3-41: Time Profile Analysis



Figure 3-42: Time Profile Analysis



Figure 3-43: Time Profile Analysis



Figure 3-44: Time Profile Analysis



Figure 3-45: Time Profile Analysis



Figure 3-46: Time Profile Analysis



Figure 3-47: Time Profile Analysis



Figure 3-48: Time Profile Analysis



Figure 3-49: Time Profile Analysis



Figure 3-50: Time Profile Analysis



Figure 3-51: Time Profile Analysis



Figure 3-52: Time Profile Analysis



Figure 3-53: Time Profile Analysis



Figure 3-54: Time Profile Analysis



4 Conclusion

The herein presented PBPK model adequately describes the pharmacokinetics of R-verapamil, S-verapamil, R-norverapamil and S-norverapamil after single and multiple administration of a variety of doses to healthy adults. Furthermore, mechanism-based CYP3A4 (auto-) inactivation on verapamil itself can be described well with the optimized parameterization.

5 References

Abernethy 1985 Abernethy DR, Schwartz JB, Todd EL. Lack of interaction between verapamil and cimetidine. Clin Pharmacol Ther. 1985 Sep;38(3):342-9. doi: 10.1038/clpt.1985.183. PMID: 4028631.

Abernethy 1993 Abernethy DR, Wainer IW, Longstreth JA, Andrawis NS (1993) Stereoselective verapamil disposition and dynamics in aging during racemic verapamil administration. The Journal of pharmacology and experimental therapeutics 266(2):904–11

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.

Blume 1983 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Blume 1994 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Blume 1987 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Blume 1989 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Blume 1990 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Blume 1994 Blume H, Mutschler E (1989) Bioäquivalenz: Qualitätsbewertung wirkstoffgleicher Fertigarzneimittel: Anleitung, Methoden, Materialien. Govi-Verlag

Boehringer 2018 Boehringer Ingelheim Pharma GmbH & Co KG (2018) The effect of potent inhibitors of drug transporters (verapamil, rifampin, cimetidine, probenecid) on pharmacokinetics of a transporter probe drug cocktail consisting of digoxin, furosemide, metformin and rosuvastatin. EudraCT 2017-001549-29. https://clinicaltrials.gov/ct2/show/record/NCT03307252, accessed: 2020-02-25

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Ratiopharm 1989 ratiopharm GmbH (2016) Fachinformation Verapamil-ratiopharm® N 40 mg / 80 mg Filmtabletten

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