Catia Marzolini1,2, Rajith Rajoli3, Manuel Battegay4,5, Luigia Elzi6, David Back3, Marco Siccardi3. 1. Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. catia.marzolini@usb.ch. 2. Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. catia.marzolini@usb.ch. 3. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 4. Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. 5. Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. 6. Division of Infectious Diseases, Regional Hospital Bellinzona, Bellinzona, Switzerland.
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.
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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