Population pharmacokinetic and pharmacodynamic modeling of evobrutinib in healthy adult participants.

Abstract

Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown therapeutic potential in relapsing multiple sclerosis. This analysis aimed to develop pharmacokinetic (PK) and pharmacodynamic (PD; BTK occupancy [BTKO]) models of evobrutinib and simulate PK and BTKO profiles under alternative dosing regimens. Data were obtained from two phase I evobrutinib studies in healthy adult participants (Japanese and non-Japanese). Overall, 2326 observations were available from 76 participants; n =42 from Study MS200527_0017 Part A received evobrutinib 25, 75, or 200 mg once-daily oral doses for 6 days while fasted; n = 18 from Study MS200527_0019 and n =16 from Study MS200527_0017 Part B received single evobrutinib 75 mg oral doses with food (low-fat meal) and while fasted. Population PK/PD modeling for evobrutinib concentrations and BTKO (fraction unbound) were performed using nonlinear mixed-effects modeling. The effect of once-daily/twice-daily regimens and doses of 10-200 mg on BTKO were simulated. A two-compartment model with sequential zero-first order absorption and first-order elimination adequately described the data. Bioavailability increased by 49% with food compared with when fasted. There was no difference in PK parameters between Japanese and non-Japanese participants. The BTKO profile of evobrutinib was described by the irreversible binding population model. The simulated percentage of participants with minimum BTKO increased in a dose-dependent manner across the BTKO thresholds of interest (70%, 80%, 90%, and 95% occupancy). Evobrutinib doses of 25 mg once-daily, 50 mg twice-daily, or 75 mg twice-daily while fasted are possible choices for further development, assuming BTKO ≥70% at trough is needed to achieve efficacy.