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



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.



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.



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.
Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. catia.marzolini@usb.ch.|Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland. catia.marzolini@usb.ch.
Catia
0000-0002-2312-7050
C
Marzolini
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Rajith
R
Rajoli
Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland.|Division of Infectious Diseases and Hospital Epidemiology, Department of Clinical Research, University Hospital of Basel, Petersgraben 4, 4031, Basel, Switzerland.
Manuel
M
Battegay
Division of Infectious Diseases, Regional Hospital Bellinzona, Bellinzona, Switzerland.
Luigia
L
Elzi
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
David
D
Back
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Marco
M
Siccardi
D000293:Adolescent; D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000378:metabolism*; D003521:Cyclopropanes; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D065696:Cytochrome P-450 CYP2C8 Inducers / Q000378:metabolism*; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005544:Forecasting; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D065696:Cytochrome P-450 CYP2C8 Inducers; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz