Safety, pharmacokinetics and pharmacodynamics of BI 705564, a highly selective, covalent inhibitor of Bruton's tyrosine kinase, in Phase I clinical trials in healthy volunteers.

Autor: Litzenburger T; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Steffgen J; Boehringer Ingelheim International GmbH, Biberach, Germany., Benediktus E; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Müller F; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Schultz A; CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany., Klein E; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Ramanujam M; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Harcken C; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Gupta A; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Wu J; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Wiebe S; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Li X; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Flack M; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Padula SJ; Boehringer Ingelheim International GmbH, Ingelheim, Germany., Visvanathan S; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Hünnemeyer A; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Hui J; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2021 Apr; Vol. 87 (4), pp. 1824-1838. Date of Electronic Publication: 2020 Nov 20.
DOI: 10.1111/bcp.14571
Abstrakt: Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism.
Methods: BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies.
Results: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564.
Conclusion: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.
(© 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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