Pharmacology Research & Perspectives (Oct 2024)
Pharmacokinetics and pharmacodynamics of the factor XIa‐inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies
Abstract
Abstract The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single‐blinded, placebo‐controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1–3 h and 4–6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose‐proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose‐dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1–4 h and 2–6 days after IV and SC administration, respectively. Anti‐drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose‐proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.
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