Objectives: Fenebrutinib (FEN) is a potent orally administered CNS penetrant Bruton's tyrosine kinase inhibitor that is highly selective and noncovalent, leading to reversible binding [1]. FEN inhibits both B-cell proliferation and microglia activation that are drivers of acute and chronic inflammation in relapsing multiple sclerosis (RMS) [2]. FENopta study (NCT05119569) is a Phase 2 study evaluating the efficacy, safety, and pharmacokinetics (PK) of FEN in patients with RMS receiving 200 mg twice-a-day oral fenebrutinib or placebo for 12 weeks. The objective of this study was to utilize a historical population pharmacokinetic (popPK) model to characterize the PK of fenebrutinib in patients with RMS [3].
Methods: The popPK analysis was conducted using previously published model constructed with PK data from two Phase 1 studies in healthy volunteers (NCT03596632, NCT02699710) and a Phase 2 study in rheumatoid arthritis patients (NCT02833350) [3]. Pooled popPK analysis was performed with addition of FENopta data to characterize fenebrutinib PK in RMS. Model evaluation was based on the inspection of graphical diagnostics, relative standard errors and plausibility of the parameter estimates.
Results: The popPK analysis dataset included a total of 4530 PK observations from 458 subjects, of which 73 subjects were patients with RMS (471 PK observations). The popPK model was a three-compartment model with linear clearance (CL/F) from the central compartment and a flexible transit compartment absorption model to describe the fenebrutinib absorption rate. Population typical values were estimated as 19.1 L/hr for CL/F, 323.8 L for volume of central compartment, and 0.757 hr for mean transit time. These results were comparable to historical popPK estimates [3].The median (1st and 3rd quantile) values of the patients with RMS were 55.5 (50.5-63.4) L/hr for CL/F, 250.5 (227.1-318.4) L for volume of central compartment, and 0.703 (0.610-0.810) hr for mean transit time. The performance and adequacy of the model to predict RMS data was demonstrated using goodness-of-fit plots including prediction-corrected visual predictive checks.
Conclusions: The final popPK model captured the observed FENopta data well and adequately described the fenebrutinib concentration versus time profiles in patients with RMS. Final popPK model was used to derive individual predictions of fenebrutinib exposure for exposure-response analysis of FENopta study.
Citations: [1] Crawford JJ, et al. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton's tyrosine kinase inhibitor in early clinical development. J Med Chem 61(6):2227–45 (2018).
[2] Krämer J, et al. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol 19, 289–304 (2023).
[3] Chan P, et al. Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis. Pharm Res 37, 25 (2020).
