Evaluation of the drug disposition of RO7049389 with in vitro data and human mass balance supported by physiologically based pharmacokinetic modelling.
RO7049389
core protein allosteric modulator
hepatitis B virus
linvencorvir
mass balance
pharmacokinetics
physiologically based pharmacokinetic modelling
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
21
05
2023
received:
05
04
2023
accepted:
24
05
2023
medline:
15
9
2023
pubmed:
2
6
2023
entrez:
2
6
2023
Statut:
ppublish
Résumé
RO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm. Participants in the clinical study (MB: Caucasian, male, n = 6; BA: Caucasian and Asian, male and female, n = 16, 8 in each ethnic groups) received oral [ The model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P-glycoprotein (~41%), direct glucuronidation via uridine 5'-diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%). These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development.
Substances chimiques
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3079-3091Informations de copyright
© 2023 British Pharmacological Society.
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