Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib : Understanding Complex Drug-Drug Interactions

© 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics..

Fenebrutinib is a CYP3A substrate and time-dependent inhibitor, as well as a BCRP and OATP1B transporter inhibitor in vitro. Physiologically-based pharmacokinetic (PBPK) modeling strategies with the ultimate goal of understanding complex drug-drug interactions (DDIs) and proposing doses for untested scenarios were developed. The consistency in the results of two independent approaches, PBPK simulation and endogenous biomarker measurement, supported that the observed transporter DDI is primarily due to fenebrutinib inhibition of intestinal BCRP, rather than hepatic OATP1B. A mechanistic-absorption model accounting for the effects of excipient complexation with fenebrutinib was used to rationalize the unexpected observation of itraconazole-fenebrutinib DDI (maximum plasma concentration (Cmax ) decreased, and area under the curve (AUC) increased). The totality of the evidence from sensitivity analysis and clinical and nonclinical data suggested that fenebrutinib is likely a sensitive CYP3A substrate. This advanced PBPK application allowed the use of model-informed approach to facilitate the development of concomitant medication recommendations for fenebrutinib without requiring additional clinical DDI studies.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:9

Enthalten in:

CPT: pharmacometrics & systems pharmacology - 9(2020), 6 vom: 15. Juni, Seite 332-341

Sprache:

Englisch

Beteiligte Personen:

Chen, Yuan [VerfasserIn]
Ma, Fang [VerfasserIn]
Jones, Nicholas S [VerfasserIn]
Yoshida, Kenta [VerfasserIn]
Chiang, Po-Chang [VerfasserIn]
Durk, Matthew R [VerfasserIn]
Wright, Matthew R [VerfasserIn]
Jin, Jin Yan [VerfasserIn]
Chinn, Leslie W [VerfasserIn]

Links:

Volltext

Themen:

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
CYP3A protein, human
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
E9L2885WUL
EC 1.14.14.1
Excipients
Fenebrutinib
Journal Article
Liver-Specific Organic Anion Transporter 1
Neoplasm Proteins
Piperazines
Pyridones
SLCO1B1 protein, human

Anmerkungen:

Date Completed 23.08.2021

Date Revised 23.08.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1002/psp4.12515

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM309670470