Population pharmacokinetic and pharmacodynamic modeling of evobrutinib in healthy adult participants

Abstract

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.