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Clinical Trial
. 2024 Oct;12(5):e70012.
doi: 10.1002/prp2.70012.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies

Zhili Dong  1 , Kensei Hashizume  2 , Frauke Friedrichs  3 , Pei Liu  4 , Toshiaki Tanaka  2 , Yuqin Liao  5
Affiliations
Clinical Trial

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies

Zhili Dong et al. Pharmacol Res Perspect. 2024 Oct.

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.

Keywords: cardiovascular pharmacology; pharmacokinetics; phase I.

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Conflict of interest statement

Frauke Friedrichs is an employee of Bayer AG. Kensei Hashizume and Toshiaki Tanaka are employees of Bayer Yakuhin, Ltd, and may own stock in the company. Zhili Dong, Pei Liu, and Yuqin Liao are employees of Bayer Healthcare Company Ltd.

Figures

FIGURE 1
FIGURE 1
Overall design of studies.
FIGURE 2
FIGURE 2
Geometric mean/standard deviation for concentrations of osocimab in plasma over 149 days in Chinese, Japanese, and Caucasiana volunteers after intravenous (IV) dosing (A) and subcutaneous (SC) dosing (B). The lower limit of quantitation (LLOQ) was 0.5000 mg/L. aEudraCT: 2014‐003816‐35 and 2017‐001937‐26.
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