Titre
Physiologically-Based Pharmacokinetic Modeling to Support the Clinical Management of Drug-Drug Interactions With Bictegravir.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Stader, F.
Auteure/Auteur
Battegay, M.
Auteure/Auteur
Marzolini, C.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1532-6535
Statut éditorial
Publié
Date de publication
2021-11
Volume
110
Numéro
5
Première page
1231
Dernière page/numéro d’article
1239
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir.
Sujets
PID Serval
serval:BIB_59A26B555DD0
PMID
Open Access
Oui
Date de création
2023-08-25T04:17:15.167Z
Date de création dans IRIS
2025-05-20T17:09:58Z
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Nom
Stader.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by-nc/4.0
Taille
537.18 KB
Format
Adobe PDF
PID Serval
serval:BIB_59A26B555DD0.P001
URN
urn:nbn:ch:serval-BIB_59A26B555DD05
Somme de contrôle
(MD5):4e138260030fad026771c7bbefccf6d7