Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.

Bettonte, Sara ORCID: 0000-0002-7532-7898, Berton, Mattia ORCID: 0000-0001-9450-2228, Stader, Felix, Battegay, Manuel and Marzolini, Catia ORCID: 0000-0002-2312-7050 (2023) Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates. European journal of drug metabolism and pharmacokinetics, 48 (4). pp. 353-362.

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Official URL: http://dx.doi.org/10.1007/s13318-023-00833-9

Abstract

<h4>Background</h4>People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.<h4>Objective</h4>The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.<h4>Methods</h4>The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.<h4>Results</h4>The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.<h4>Conclusions</h4>Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.

Item Type:	Article
Uncontrolled Keywords:	Humans, Rifabutin, Rifampin, Glucuronosyltransferase, Drug Interactions, Female, Male, Cytochrome P-450 CYP3A, Raltegravir Potassium
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	29 Feb 2024 09:20
Last Modified:	29 Feb 2024 09:20
DOI:	10.1007/s13318-023-00833-9
Open Access URL:	https://doi.org/10.1007/s13318-023-00833-9
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178992