Safety, pharmacokinetics and pharmacodynamics of BI 655064 in phase 1 clinical trials in healthy Chinese and Japanese subjects.

Autor: Tsuda Y; Nippon Boehringer Ingelheim Co. Ltd, Kobe, Japan., Grimaldi C; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA., Huang F; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA., Benediktus E; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Yagi N; Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan., Padula SJ; Boehringer Ingelheim International GmbH, Ingelheim, Germany., Jang IJ; Seoul National University Hospital Clinical Trials Center, Seoul, Korea., Steffgen J; Boehringer Ingelheim International GmbH, Biberach, Germany.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2021 Apr; Vol. 87 (4), pp. 2000-2013. Date of Electronic Publication: 2020 Dec 09.
DOI: 10.1111/bcp.14601
Abstrakt: Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80-240 mg and multiple dosing of 240 mg once weekly over 4 weeks.
Methods: Two phase 1, double-blind, placebo-controlled studies were conducted (single-rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064.
Results: BI 655064 showed good overall tolerability following single-dose administration of 80-240 mg and repeated administration of 240 mg BI 655064 over 4 weeks. More Chinese subjects reported adverse events compared with Japanese subjects following single-dose administration (59.4% vs 3.1%). BI 655064 exhibited nonlinear, saturable kinetics, with higher doses resulting in slower apparent clearance (0.514-0.713 mL min -1 ), and disproportionately higher total exposure (AUC 0-inf ; 5610-7780 μg·h mL -1 ) and maximum plasma concentration (15 700-21 300 ng mL -1 ) with 240 mg BI 655064. Ninety percent inhibition of CD40 RO was achieved with doses ≥120 mg, and a direct relationship between BI 655064 plasma concentration and inhibition of CD40 RO was observed. Most subjects had a positive treatment-emergent antidrug antibody response.
Conclusions: BI 655064 pharmacokinetic and safety profiles in East Asian male subjects were consistent with those observed in a Western population. No adjustments in the BI 655064 dosing recommendations are warranted for future clinical trials.
(© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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