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Population Pharmacokinetics, Efficacy Exposure-Response Analysis

Authors
  • Chan, Phyllis1
  • Yu, Jiajie1
  • Chinn, Leslie1
  • Prohn, Marita2
  • Huisman, Jan2
  • Matzuka, Brett3
  • Hanley, William4
  • Tuckwell, Katie5
  • Quartino, Angelica1
  • 1 Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA , South San Francisco (United States)
  • 2 qPharmetra, Nijmegen, Netherlands , Nijmegen (Netherlands)
  • 3 qPharmetra, Cary, North Carolina, USA , Cary (United States)
  • 4 Former Genentech employee, currently of Seattle Genetics, South San Francisco, California, USA , South San Francisco (United States)
  • 5 Early Clinical Development, Genentech, South San Francisco, California, USA , South San Francisco (United States)
Type
Published Article
Journal
Pharmaceutical Research
Publisher
Springer-Verlag
Publication Date
Jan 06, 2020
Volume
37
Issue
2
Identifiers
DOI: 10.1007/s11095-019-2752-y
Source
Springer Nature
Keywords
License
Green

Abstract

PurposeFenebrutinib (GDC-0853), a Bruton’s tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data.MethodsPopulation pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed based on the Phase 2 data.ResultsPopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an Emax function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments.ConclusionsOur multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial.

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