Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

• Published in: Pharmaceutical research Vol. 37; no. 2; p. 25
• Main Authors: Chan, Phyllis, Yu, Jiajie, Chinn, Leslie, Prohn, Marita, Huisman, Jan, Matzuka, Brett, Hanley, William, Tuckwell, Katie, Quartino, Angelica
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2020; Springer; Springer Nature B.V
• Subjects: Adalimumab; Arthritis; B cells; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Bruton's tyrosine kinase; Clinical trials; Dose-response effects; Drug development; Enzyme inhibitors; Medical Law; Medical research; Medicine, Experimental; Meta-analysis; Monoclonal antibodies; Oral administration; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Protein-tyrosine kinase; Research Paper; Rheumatoid arthritis; Rheumatoid factor; Tyrosine; Bruton’s tyrosine kinase (BTK) inhibitor; model-based meta-analysis; rheumatoid arthritis; exposure-response; population pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-019-2752-y

Purpose Fenebrutinib (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. Methods Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. Results PopPK 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 E max 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. Conclusions Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial.