Population pharmacokinetics and exposure-response modelling of firsekibart (GenSci048) in patients with acute gout flare: Implications for fixed-dose optimization.

Abstract

Firsekibart (formerly GenSci048 or genakumab) is a humanized anti-IL-1β monoclonal antibody developed for acute gouty flares in patients unsuitable for standard therapies. This study characterized its population pharmacokinetics (PopPK), assessing covariate effects, and established exposure-response (E-R) relationships to guide dosing. Data from four clinical trials involving 296 subjects (2287 concentrations) were pooled to develop a PopPK model using NONMEM with stepwise covariate screening. A one-compartment model with sequential zero- and first-order absorption was utilized. E-R analyses were conducted to assess efficacy (dVAS_72h, defined as achieving ≥50% reduction in Visual Analog Scale [VAS] scores from baseline measured at 72 h) and safety (dyslipidaemia/hepatic dysfunction/infectious and invasive diseases) using logistic regression. Body weight significantly affected clearance and distribution volume. Hepatic or renal impairment caused exposure differences of less than 27%. No exposure-dependent safety trends were identified across the evaluated exposure range. Although exposure-response trends were observed across the broader dose range, the gradient within the exposure range achieved by 195-200 mg was shallow, consistent with a plateau. Simulations indicated that at the 200-mg dose, more than 95% of patients attained exposures associated with at least 85% probability of achieving dVAS_72h. Firsekibart also markedly reduced flare recurrence over 12 weeks compared with the control group. Firsekibart demonstrated predictable pharmacokinetics, a favourable safety profile, and robust efficacy coverage at the 200-mg fixed dose. These findings support fixed-dosing for patients with acute gout flares who are intolerant of, unsuitable for, or inadequately responsive to standard-of-care therapies.