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Building and evaluation of a PBPK model for Itraconazole in healthy adults

Version 2.0-OSP12.3
based on Model Snapshot and Evaluation Plan https://github.com/Open-Systems-Pharmacology/Itraconazole-Model/releases/tag/v2.0
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

Itraconazole is a triazole agent prescribed for the treatment of fungal infections. It is predominantly metabolized by CYP3A4, resulting in the sequential formation of several metabolites, starting with the major metabolite hydroxy-itraconazole, followed by keto-itraconazole and N-desalkyl-itraconazole. All three metabolites are further metabolized by CYP3A4 and parent and metabolites are reported to competitively inhibit CYP3A4 (Isoherranen 2004). Therefore, the metabolites inhibit their own formation and itraconazole inhibits further conversion of its metabolites by CYP3A4. Itraconazole has been proposed as one of the most appropriate CYP3A4 inhibitors for clinical DDI studies, to replace the currently no longer recommended CYP3A4 inhibitor drug ketoconazole.

The herein presented model represents an update of the itraconazole model publisdhed by Hanke et al. (Hanke 2018). The model was originally established using various clinical studies, covering a dosing range from 100 to 200 mg in different formulations (solution and capsules), administered under fasted conditions or together with food. Although the plasma concentrations of keto-itraconazole and N-desalkyl-itraconazole are lower than those of itraconazole and hydroxy-itraconazole, N-desalkyl-itraconazole is reported to be a very potent inhibitor in vitro, and integration of the two further metabolites into the model with their inhibitory effects enabled the description the strong non-linearity and plasma accumulation of itraconazole. The model applies sequential metabolism of itraconazole to hydroxy-itraconazole to keto-itraconazole to N-desalkyl-itraconazole by CYP3A4, including competitive inhibition of CYP3A4 by the parent drug and all three metabolites, and glomerular filtration. Competitive inhibition of P-gp was included for itracaonazole.

In comparison to the published version by Hanke et al. 2018 (Hanke 2018), the dissolution and solubility has been optimized and updated for the administration of itraconazole capsules in fasted state (by integrating additional data (Jalava 1997) into the optimization routine).

2 Methods

2.1 Modeling Strategy

The general concept of building a PBPK model has previously been described by Kuepfer et al. (Kuepfer 2016). Relevant information on anthropometric (height, weight) and physiological parameters (e.g. blood flows, organ volumes, binding protein concentrations, hematocrit, cardiac output) in adults was gathered from the literature and has been previously published (Willmann 2007). The information was incorporated into PK-Sim® and was used as default values for the simulations in adults.

The applied activity and variability of plasma proteins and active processes that are integrated into PK-Sim® are described in the publicly available PK-Sim® Ontogeny Database Version 7.3 (PK-Sim Ontogeny Database Version 7.3) or otherwise referenced for the specific process.

First, a mean model including sequential metabolism of itraconazole to hydroxy-itraconazole to keto-itraconazole to N-desalkyl-itraconazole by CYP3A4 was built using clinical data from single dose and multiple dose studies with intravenous and oral administration (solution, fasted state) of itraconazole. Hereby, competitive inhibition of CYP3A4 was considered for all four compounds. The mean PBPK model was developed using a typical European individual. The relative tissue-specific expressions of enzymes predominantly being involved in the metabolism of midazolam (CYP3A4) were considered.

A specific set of parameters (see below) was optimized 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.

Once the appropriate structural model was identified, additional parameters for different administration states (solution fed, capsule fasted and capsule fed versus the reference state solution fasted) were empirically optimized. Clinical data suggest that the bioavailability of itraconazole is enhanced when an oral solution is given in the fasted state compared to fed state (Van de Welde 1996, Barone 1998a). In contrast, a meal significantly enhances the amount of itraconazole absorbed after administrations of capsules (in comparison to fasted state administrations of capsules) (Barone 1993a). To reflect these observations, relevant parameters, in particular solubility and those describing dissolution kinetics (of capsules), were assumed to be variable between these four scenarios and were independently identified using the Parameter Identification module provided in PK-Sim®.

Details about compound properties (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

2.2.1 In vitro and physicochemical data

A literature search was performed to collect available information on physicochemical properties of itraconazole and metabolites. The obtained information from literature is summarized in the table below and was used for model building. Note that not all parameters were used in the final model. A list of final model parameters is provided below in later sections.

Itraconazole

Parameter Unit Value Source Description
MW g/mol 705.633 DrugBank DB01167 Molecular weight
pKa,base 3.7 Heykants 1989 acid dissociation constant of conjugate acid; compound type: base
Solubility (pH) mg/L 8.0
(6.5)		 Taupitz 2013 Solubility in FaSSIF (fasted state simulated intestinal fluid)
logP 5.66 Heykants 1989 Partition coefficient between octanol and water
fu % 0.2 Heykants 1989 Fraction unbound in plasma
% 0.2 Riccardi 2015 Fraction unbound in plasma
% 1.58 Ishigam 2001 Fraction unbound in plasma
% 3.6 Templeton 2008 Fraction unbound in plasma
Vmax, Km CYP3A4 pmol/min/nmol,
nmol/L		 270
3.9		 Isoherranen 2004 CYP3A4 supersomes Michaelis-Menten kinetics
Ki CYP3A4 nmol/L 1.3 Isoherranen 2004 CYP3A4 inhibition constant
Ki P-gp nmol/L 8.0 Shityakov 2014 P-gp inhibition constant

Hydroxy-itraconazole

Parameter Unit Value Source Description
MW g/mol 721.633 DrugBank DBMET00374 Molecular weight
logP 4.5 PubChem CID 108222 Partition coefficient between octanol and water, computed by XLogP3 3.0
fu % 0.5 Templeton 2008 Fraction unbound in plasma
% 1.7 Riccardi 2015 Fraction unbound in plasma
% 2.12 Chen 2016 Fraction unbound in plasma
Vmax, Km CYP3A4 pmol/min/nmol,
nmol/L		 543
27		 Isoherranen 2004 CYP3A4 supersomes Michaelis-Menten kinetics
Ki CYP3A4 nmol/L 14.4 Isoherranen 2004 CYP3A4 inhibition constant

Keto-itraconazole

Parameter Unit Value Source Description
MW g/mol 719.617 PubChem CID 53865186 Molecular weight
logP 4.5 PubChem CID 53865186 Partition coefficient between octanol and water, computed by XLogP3 3.0
fu % 1.0 Riccardi 2015 Fraction unbound in plasma
% 5.3 Templeton 2008 Fraction unbound in plasma
Vmax, Km CYP3A4 pmol/min/nmol,
nmol/L		 86.9
1.4		 Isoherranen 2004 CYP3A4 supersomes Michaelis-Menten kinetics
IC50 CYP3A4† nmol/L 7.0 Isoherranen 2004 CYP3A4 inhibition constant for half maximal inhibitory concentration at constant substrate concentration

† The IC50 values was converted to a Ki value via Cheng-Prusoff equation (Chen 1973) with a substrate (midazolam) concentration of 1 µmol/L and an assumed substrate (midazolam) Km value of 2.73 µmol/L: 5.12 nmol/L

N-Desalkyl-itraconazole

Parameter Unit Value Source Description
MW g/mol 649.527 PubChem CID 53789808 Molecular weight
logP 4.2 PubChem CID 53789808 Partition coefficient between octanol and water, computed by XLogP3 3.0
fu % 1.1 Riccardi 2015 Fraction unbound in plasma
% 1.2 Templeton 2008 Fraction unbound in plasma
IC50 CYP3A4† nmol/L 0.44 Isoherranen 2004 CYP3A4 inhibition constant for half maximal inhibitory concentration at constant substrate concentration

† The IC50 values was converted to a Ki value via Cheng-Prusoff equation (Chen 1973) with a substrate (midazolam) concentration of 1 µmol/L and an assumed substrate (midazolam) Km value of 2.73 µmol/L: 0.32 nmol/L

2.2.2 Clinical data

A literature search was performed to collect available clinical data on itraconazole and its metabolites in adults. The itraconazole model was built and verified using various clinical studies, covering a dosing range of 100 to 200 mg with different formulations (solution vs. capsule), administered under fasting conditions or together with food.

The following dosing senarios were simulated and compared to respective data:

Route Formulation Food state Dose
[mg]		 Dosing PK Data Used for† Reference
iv - - 100 SD Itraconazole mv Heykants 1989
200 OD Itraconazole
Hydroxy-Itr.		 mbb Mouton 2006
po solution fasted 100 SD Itraconazole mbb Van de Velde 1996
Itraconazole
Hydroxy-Itr.		 mbb Van Peer 1989
OD Itraconazole
Hydroxy-Itr.
Keto-Itr.
N-Desalkyl-Itr.		 mbb Templeton 2008
200 OD Itraconazole
Hydroxy-Itr.		 mbb Barone 1998a
fed 100 SD Itraconazole
Hydroxy-Itr.		 mbe Van de Velde 1996
Itraconazole mbe Heykants 1989
200 SD Itraconazole
Hydroxy-Itr.		 mbe Barone 1998b
OD Itraconazole
Hydroxy-Itr.		 mbe Barone 1998a
capsule fasted 100 SD Itraconazole mbe Van Peer 1989
BID Itraconazole mv Kivistö 1997
200 SD Itraconazole
Hydroxy-Itr.		 mbe Barone 1993
Itraconazole mv Neuvonen 1996
OD Itraconazole mbe Jalava 1997
Itraconazole mbe Olkkola 1994
Itraconazole mv Varhe 1994
fed 100 SD Itraconazole mbe Van Peer 1989
OD Itraconazole mbe Van Peer 1989
Itraconazole mv Hardin 1988
200 SD Itraconazole
Hydroxy-Itr.		 mbe Barone 1993
Itraconazole
Hydroxy-Itr.		 mbe Barone 1998b
Itraconazole mv Neuvonen 1996
200 OD Itraconazole mv Hardin 1988
BID Itraconazole mbe Barone 1993
Itraconazole
Hydroxy-Itr.		 mv Hardin 1988

† mbb model building basic: used to inform the basic model parameters (see Section 2.3.5); mbe model building extended: used to inform solubility and, if applicable, formulation-depenendent parameters only (see Section 2.3.5); mv model verification only

2.3 Model Parameters and Assumptions

2.3.1 Absorption

Clinical data suggest that the bioavailability of itraconazole is enhanced when an oral solution is given in the fasted state compared to fed state (Van de Welde 1996, Barone 1998a). In contrast, a meal significantly enhances the amount of itraconazole absorbed after administrations of capsules (in comparison to fasted state administrations of capsules) (Barone 1993a). Thus, four different scenarios can be identified: solution fasted, solution fed, capsule fasted and capsule fed. The solution fasted scenario was considered to be the reference scenario.

Herein, the model parameter Specific intestinal permeability was optimized to best match clinical data (see Section 2.3.5). The default solubility was assumed to be the measured value in FaSSIF (fasted state simulated intestinal fluid; see Section 2.2.1).

In a next step, the solubility was optimized for the solution fed scenario (in comparison to solution fasted).

Then, for the scenarios capsule fasted and capsule fed, solubility and the dissolution rate of the capsules (implemented via an empirical Weibull dissolution) were optimized.

The results of the optimization can be found in Section 2.3.5.

2.3.2 Distribution

Various values for the fraction unbound of itraconazole have been reported in literature, ranging from 0.2 to 3.6% (see Section 2.2.1). For this model, the final value was optimized within this range to best match observed clinical data (see Section 2.3.5). For the metabolites, the measured values reported by Riccardi et al. (Riccardi 2015) were incorporated into the model. It was assumed that the major binding partner is albumin.

No pKa values were reported for the three metabolites. Here, it was assumed that the metabolites are similar to the parent drug and the reported basic pKa value of 3.7 was applied (see also Section 2.2.1)

An important parameter influencing the resulting volume of distribution is lipophilicty. The reported experimental or predicted logP values served as starting values for the four compounds. Finally, the model parameters Lipophilicity were optimized to match best clinical data (see also Section 2.3.5).

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 for itraconazole and its metabolites.

2.3.3 Metabolism and Elimination

Metabolic pathways via CYP3A4 were implemented in the model via Michaelis-Menten kinetics for all four compounds. If available, in vitro determined unbound Km values (Isoherranen 2004) served as starting values. Respective kcat values were optimized to best match clinical data (see also Section 2.3.5).

The CYP3A4 expression profile is based on high-sensitivity real-time RT-PCR (Nishimura 2013). Absolute tissue-specific concentrations were obtained by considering the respective absolute concentration in the liver. The PK-Sim® Ontogeny Database Version 7.3 provides a default value for CYP3A4 reference concentration in the liver (compare Rodrigues 1999 and assume 40 mg protein per gram liver).

Additionally, for all four compounds a renal clearance (assumed to be driven by glomerular filtration) was implemented.

2.3.4 DDI Parameters

The following subsections describe the model input for DDI-related parameters, i.e. inhibition of certain enzymes and transporters, for which itraconazole may act in a perpetrator role. Verification of these model parameters and linked processes in combination with sensitive CYP3A4 / P-gp substrates is not evaluated in this report. Applications are assessed in specific use cases and reported elsewhere. Note, however, that the competitive CYP3A4 inhibition of the four compounds results in inhibition of metabolite formation (of hydroxy-itraconazole, keto-itraconazole, N-desalkyl-itraconazole) and the metabolism of N-desalkyl-itraconazole. This effectively contributes to the PK non-linearity of itraconazole and its metabolites, especially after multiple doses.

CYP3A4 inhibition

In vitro determined unbound Ki values for itraconazole and hydroxy-itraconazole (Isoherranen 2004) served directly as model input (see Section 2.2.1).

In vitro determined unbound IC50 values for keto-itraconazole and N-desalkyl-itraconazol (Isoherranen 2004) were converted to Ki values via the Cheng-Prusoff equation (Chen 1973) with a substrate (midazolam) concentration of 1 µmol/L and an assumed substrate (midazolam) Km value of 2.73 µmol/L (see Section 2.2.1).

P-gp inhibition

An in vitro determined Ki values for itraconazole (Shityakov 2014) served directly as model input (see Section 2.2.1).

2.3.5 Automated Parameter Identification

This is the result of the final parameter identification for the basic model:

Compound Model Parameter Optimized Value Unit
Itraconazole Lipophilicity 4.62 Log Units
Specific intestinal permeability 5.33E-05 dm/min
Fraction unbound (plasma, reference value) 0.6 %
Km (CYP3A4) 2.07 nmol/L
kcat (CYP3A4) 0.040 1/min
Hydroxy-Itr. Lipophilicity 3.72 Log Units
Fraction unbound (plasma, reference value) 1.7 FIXED (see Section 2.2.1) %
Km (CYP3A4) 4.17 nmol/L
kcat (CYP3A4) 0.020 1/min
Keto-Itr. Lipophilicity 4.21 Log Units
Fraction unbound (plasma, reference value) 1.0 FIXED (see Section 2.2.1) %
Km (CYP3A4) 2.22 nmol/L
kcat (CYP3A4) 0.393 1/min
N-Desalkyl-Itr. Lipophilicity 5.18 Log Units
Fraction unbound (plasma, reference value) 1.1 FIXED (see Section 2.2.1) %
Km (CYP3A4) 0.63 nmol/L
kcat (CYP3A4) 0.061 1/min

This is the result of the final parameter identification for the solubility and, in case of capsule administrations, the dissolution parameters of an empirical Weibull function according to the different administration scenarios of itraconazole:

Scenario Model Parameter Optimized Value Unit
Solution fasted Solubility at reference pH 8.0 FIXED (see Section 2.2.1) mg/L
Solution fed Solubility at reference pH 1.58 mg/L
Capsule fasted Solubility at reference pH 0.97 mg/L
Dissolution time (50% dissolved) 406 min
Dissolution shape 1.43
Capsule fed Solubility at reference pH 0.70 mg/L
Dissolution time (50% dissolved) 139 min
Dissolution shape 0.82

3 Results and Discussion

The PBPK model for itraconazole was developed and verified with clinical pharmacokinetic data.

The model was built and evaluated covering data from various clinical studies, covering a dosing range of 100 to 200 mg in different formulations (solution vs. capsule), administered under fasting conditions or together with food.

The model quantifies metabolism via CYP3A4 and inhibition of CYP3A4.

The next sections show:

  1. the final model input 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: Itraconazole

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 8 mg/l Publication-Taupitz et al. 2013 Solution fasted (Taupitz et al. 2013) True
Reference pH 6.5 Publication-Taupitz et al. 2013 Solution fasted (Taupitz et al. 2013) True
Solubility at reference pH 1.58 mg/l Solution fed False
Reference pH 6.5 Solution fed False
Solubility at reference pH 0.9728307177 mg/l Parameter Identification-Parameter Identification-Value updated from 'Capsule fasted' on 2019-05-15 12:25 Capsule fasted False
Reference pH 6.5 Capsule fasted False
Solubility at reference pH 0.7 mg/l Capsule fed False
Reference pH 6.5 Capsule fed False
Lipophilicity 4.624 Log Units Parameter Identification-Fit Fit True
Fraction unbound (plasma, reference value) 0.6016197247 % Templeton, 2008 True
Specific intestinal permeability (transcellular) 5.3261558344E-05 dm/min Parameter Identification-Fit Fit True
Cl 2
Is small molecule Yes
Molecular weight 705.633 g/mol
Plasma protein binding partner Albumin

Calculation methods

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

Processes

Metabolizing Enzyme: CYP3A4-Isoherranen 2004

Molecule: CYP3A4

Metabolite: Hydroxy-Itraconazole

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 0.27 pmol/min/pmol rec. enzyme Publication-Isoherranen 2004
Km 2.0688492598 nmol/l Publication-Isoherranen 2004
kcat 0.0402937875 1/min Unknown
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1 Publication-Isoherranen 2004
Inhibition: CYP3A4-Isoherranen, 2004

Molecule: CYP3A4

Parameters
Name Value Value Origin
Ki 1.3 nmol/l Parameter Identification-Isoherranen, 2004
Inhibition: ABCB1-Shityakov 2014

Molecule: ABCB1

Parameters
Name Value Value Origin
Ki 0.008 µmol/l Publication-Shityakov 2014

Compound: Hydroxy-Itraconazole

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 1 mg/l No value available True
Reference pH 7 No value available True
Lipophilicity 3.718 Log Units Fit True
Fraction unbound (plasma, reference value) 1.7 % Publication-Templeton, 2008 Templeton, 2008 True
Cl 2
Is small molecule Yes
Molecular weight 721.633 g/mol
Plasma protein binding partner Albumin

Calculation methods

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

Processes

Metabolizing Enzyme: CYP3A4-Isoherranen 2004

Molecule: CYP3A4

Metabolite: Keto-Itraconazole

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 0.543 nmol/min/pmol rec. enzyme Publication-Isoherranen 2004
Km 4.1716224833 nmol/l Publication-Isoherranen 2004
kcat 0.0203370845 1/min Unknown
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1 Publication-Isoherranen, 2004
Inhibition: CYP3A4-Isoherranen, 2004

Molecule: CYP3A4

Parameters
Name Value Value Origin
Ki 14.4 nmol/l Publication-Isoherranen, 2004
Inhibition: OATP1B1-Tuerk 2019

Molecule: OATP1B1

Parameters
Name Value Value Origin
Ki 0.0177818488 µmol/l Parameter Identification-Parameter Identification
Inhibition: OATP1B3-Tuerk 2019

Molecule: OATP1B3

Parameters
Name Value Value Origin
Ki 0.0111606334 µmol/l Parameter Identification-Parameter Identification

Compound: Keto-Itraconazole

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 1 mg/l No value available True
Reference pH 7 No value available True
Lipophilicity 4.2109086248 Log Units Fit True
Fraction unbound (plasma, reference value) 1 % Publication-Templeton, 2008 Templeton, 2008 True
Cl 2
Is small molecule Yes
Molecular weight 719.617 g/mol
Plasma protein binding partner Albumin

Calculation methods

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

Processes

Metabolizing Enzyme: CYP3A4-Isoherranen 2004

Molecule: CYP3A4

Metabolite: N-desalkyl-Itraconazole

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 0.0869 pmol/min/pmol rec. enzyme Publication-Isoherranen 2004
Km 2.2214874285 nmol/l Publication-Isoherranen 2004
kcat 0.3933927416 1/min Unknown
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1 Publication-Isoherranen 2004
Inhibition: CYP3A4-Isoherranen, 2004

Molecule: CYP3A4

Parameters
Name Value Value Origin
Ki 5.12 nmol/l Publication-Isoherranen 2004

Compound: N-desalkyl-Itraconazole

Parameters

Name Value Value Origin Alternative Default
Solubility at reference pH 1 mg/l No value available True
Reference pH 7 No value available True
Lipophilicity 5.1837535822 Log Units Fit True
Fraction unbound (plasma, reference value) 1.1 % Publication-Templeton, 2008 Templeton, 2008 True
Cl 2
Is small molecule Yes
Molecular weight 649.527 g/mol
Plasma protein binding partner Albumin

Calculation methods

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

Processes

Metabolizing Enzyme: CYP3A4-Isoherranen 2004

Molecule: CYP3A4

Parameters
Name Value Value Origin
In vitro Vmax/recombinant enzyme 0 nmol/min/pmol rec. enzyme
Km 0.6284266369 nmol/l Publication-Isoherranen 2004
kcat 0.0605873508 1/min Unknown
Systemic Process: Glomerular Filtration-GFR

Species: Human

Parameters
Name Value Value Origin
GFR fraction 1 Publication-Isoherranen 2004
Inhibition: CYP3A4-Isoherranen, 2004

Molecule: CYP3A4

Parameters
Name Value Value Origin
Ki 0.32 nmol/l Publication-Isoherranen, 2004

Formulation: Capsule fasted

Type: Weibull

Parameters

Name Value Value Origin
Dissolution time (50% dissolved) 406.3001802552 min Parameter Identification-Parameter Identification-Value updated from 'Capsule fasted' on 2019-05-15 12:25
Lag time 0 min
Dissolution shape 1.4297720052 Parameter Identification-Parameter Identification-Value updated from 'Capsule fasted' on 2019-05-15 12:25
Use as suspension Yes

Formulation: Capsule fed

Type: Weibull

Parameters

Name Value Value Origin
Dissolution time (50% dissolved) 138.95 min
Lag time 0 min
Dissolution shape 0.82
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 2.2.2.

The plot show observed versus simulated plasma concentration and second weighted residuals versus time for itraconazole, hydroxy-itraconazole, keto-itraconazole and N-desalkyl-itraconazole.

Table 3-1: GMFE for Itraconazole concentration in plasma

Group GMFE
Itraconazole iv 1.29
Itraconazole po capsule fasted 1.74
Itraconazole po capsule fed 1.57
Itraconazole po solution fasted 1.54
Itraconazole po solution fed 1.46
All 1.54



Figure 3-1: Itraconazole concentration in plasma



Figure 3-2: Itraconazole concentration in plasma



Table 3-2: GMFE for Hydroxy-Itraconazole concentration in plasma

Group GMFE
Itraconazole iv 1.21
Itraconazole po capsule fasted 1.68
Itraconazole po capsule fed 1.95
Itraconazole po solution fasted 1.38
Itraconazole po solution fed 1.48
All 1.50



Figure 3-3: Hydroxy-Itraconazole concentration in plasma



Figure 3-4: Hydroxy-Itraconazole concentration in plasma



Table 3-3: GMFE for Keto-Itraconazole concentration in plasma

Group GMFE
Itraconazole po solution fasted 1.66



Figure 3-5: Keto-Itraconazole concentration in plasma



Figure 3-6: Keto-Itraconazole concentration in plasma



Table 3-4: GMFE for N-desalkyl-Itraconazole concentration in plasma

Group GMFE
Itraconazole po solution fasted 1.53



Figure 3-7: N-desalkyl-Itraconazole concentration in plasma



Figure 3-8: N-desalkyl-Itraconazole concentration in plasma



3.3 Concentration-Time Profiles

Simulated versus observed concentration-time profiles of all data listed in Section 2.2.2 are presented below.

Figure 3-9: 100 mg IV SD - Plasma



Figure 3-10: 200 mg IV MD - Plasma



Figure 3-11: po 100 mg SD caps fast - Plasma



Figure 3-12: po 200 mg MD OD caps fast - Plasma



Figure 3-13: po 100 mg MD BID caps fast - Plasma



Figure 3-14: po 200 mg SD caps fast - Plasma



Figure 3-15: po 100 mg MD OD caps fed 1 - Plasma



Figure 3-16: po 100 mg MD OD caps fed 2 - Plasma



Figure 3-17: po 100 mg SD caps fed - Plasma



Figure 3-18: po 200 mg MD BID caps fed 1 - Plasma



Figure 3-19: po 200 mg MD BID caps fed 2 - Plasma



Figure 3-20: po 200 mg MD OD caps fed - Plasma



Figure 3-21: po 200 mg SD caps fed - Plasma



Figure 3-22: po 200 mg SD caps fed 2 - Plasma



Figure 3-23: po 100 mg MD OD sol fast - Plasma



Figure 3-24: po 100 mg SD sol fast - Plasma



Figure 3-25: po 200 mg MD OD sol fast - Plasma



Figure 3-26: po 100 mg SD sol fed - Plasma



Figure 3-27: po 200 mg MD OD sol fed - Plasma



Figure 3-28: po 200 mg SD sol fed - Plasma



4 Conclusion

The herein presented PBPK model adequately describes the pharmacokinetics of itraconazole in adults.

In particular, the model includes the sequential metabolites hydroxy-itraconazole, keto-itraconazola and N-desalkyl-itraconazole - all of them formed by CYP3A4. The model applies competitive inhibition of CYP3A4 by itraconzaole and the three metabolites. Thus, the model is fit for purpose to be applied for the investigation of drug-drug interactions with regard to strong CYP3A4 inhibition.

5 References

Barone 1993 Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother. 1993 Apr;37(4):778-84.

Barone 1998a Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L. Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers. Pharmacotherapy. 1998 Mar-Apr;18(2):295-301.

Barone 1998b Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L. Enhanced bioavailability of itraconazole in hydroxypropyl-beta-cyclodextrin solution versus capsules in healthy volunteers. Antimicrob Agents Chemother. 1998 Jul;42(7):1862-5.

Chen 2016 Chen Y, Ma F,, Lu T, Budha N, Jin JY, Kenny JR, Wong H,, Hop CE, Mao J. Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction. Clin Pharmacokinet. 2016 Jun;55(6):735-49.

Cheng 1973 Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099-108.

DrugBank DB01167 (https://www.drugbank.ca/drugs/DB01167)

DrugBank DBMET00374 (https://www.drugbank.ca/metabolites/DBMET00374)

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PK-Sim Ontogeny Database Version 7.3 (https://github.com/Open-Systems-Pharmacology/OSPSuite.Documentation/blob/38cf71b384cfc25cfa0ce4d2f3addfd32757e13b/PK-Sim%20Ontogeny%20Database%20Version%207.3.pdf)

PubChem CID 108222 (https://pubchem.ncbi.nlm.nih.gov/compound/Hydroxy-Itraconazole)

PubChem CID 53865186 (https://pubchem.ncbi.nlm.nih.gov/compound/Keto-Itraconazole)

PubChem CID 53789808 (https://pubchem.ncbi.nlm.nih.gov/compound/169437521#section=Computed-Properties)

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