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Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes

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Abstract

Background

Antiretroviral drugs are among the therapeutic agents with the highest potential for drug–drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously.

Methods

This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug–concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data.

Results

The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism.

Conclusion

PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.

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Authors and Affiliations

  1. Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland

    Catia Marzolini & Manuel Battegay

  2. Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland

    Catia Marzolini & Manuel Battegay

  3. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Rajith Rajoli, David Back & Marco Siccardi

  4. Division of Infectious Diseases, Regional Hospital Bellinzona, Bellinzona, Switzerland

    Luigia Elzi

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  1. Catia Marzolini
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  2. Rajith Rajoli
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  3. Manuel Battegay
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  4. Luigia Elzi
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  5. David Back
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  6. Marco Siccardi
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Correspondence to Catia Marzolini.

Ethics declarations

CM has been supported by a Grant of the University of Basel (Grant DMS2265) and has received educational Grants from AbbVie, Gilead, and Bristol-Myers-Squibb for her clinical service on drug–drug interactions, and research funding from Janssen. DB has received research Grants from Merck, AbbVie, Gilead, ViiV, Bristol-Myers-Squibb, and Janssen, and travel bursaries from Gilead, ViiV, AbbVie, and Janssen. MS has received research funding from ViiV and Janssen. LE, MB, and RR declare no conflicts of interest.

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Marzolini, C., Rajoli, R., Battegay, M. et al. Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes. Clin Pharmacokinet 56, 409–420 (2017). https://doi.org/10.1007/s40262-016-0447-7

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