Physiologically-Based Pharmacokinetic Model-Informed Drug Development for Fenebrutinib: Understanding Complex Drug-Drug Interactions.
CPT Pharmacometrics Syst Pharmacol
; 9(6): 332-341, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32383787
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Piridonas
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Transportador 1 de Ânion Orgânico Específico do Fígado
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Citocromo P-450 CYP3A
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Inibidores do Citocromo P-450 CYP3A
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
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Intestinos
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Fígado
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Modelos Biológicos
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Proteínas de Neoplasias
Tipo de estudo:
Guideline
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article