Dataset Information

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.

ABSTRACT:

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.

SUBMITTER: Litzenburger T

PROVIDER: S-EPMC9290462 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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.

Litzenburger Tobias T Steffgen Jürgen J Benediktus Ewald E Müller Fabian F Schultz Armin A Klein Elliott E Ramanujam Meera M Harcken Christian C Gupta Alpana A Wu Jing J Wiebe Sabrina S Li Xiujiang X Flack Mary M Padula Steven J SJ Visvanathan Sudha S Hünnemeyer Andreas A Hui Jianan J

British journal of clinical pharmacology 20201120 4

<h4>Aims</h4>To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism.<h4>Methods</h4>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 ...[more]

PMID: 32986868

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Project description:BackgroundS-pindolol has metabolic effects of potential benefit in cancer cachexia: reduced catabolism through nonselective β-blockade; increased anabolism through partial β2 receptor agonism; and increased appetite and reduced fatigue through central 5-hydroxytryptamine/serotonin receptor activity. A Phase 2a clinical trial demonstrated that S-pindolol can reverse weight loss and improve fat-free mass in patients with cancer-related weight loss. A comparative phase I bioavailability study of S-pindolol and racemic pindolol was performed to support the development of S-pindolol in cancer cachexia.MethodsThis two-part study assessed the comparative bioavailability and pharmacokinetics of single doses of S-pindolol benzoate (ACM-001.1) or pindolol (Part 1) and the steady-state pharmacokinetics and pharmacodynamics of multiple doses of ACM-001.1 and pindolol (Part 2) in healthy volunteers (NCT06028321). ACM-001.1 5, 10 and 15 mg and pindolol 15, 20 and 30 mg were tested. In Part 1, subjects were randomised to ACM-001.1 15 mg followed after a 48-h washout period by pindolol 30 mg, or the reverse sequence; another group received pindolol 15 mg. Subjects in Part 2 were randomised to pindolol 20 mg twice-daily or ACM-001.1 5, 10 or 15 mg twice-daily for 4 days. Bioavailability, pharmacokinetics, pharmacodynamics, potential for and extent of stereoconversion, and tolerability were assessed.ResultsParts 1 and 2 included 24 and 27 healthy volunteers, respectively. ACM-001.1 had predictable pharmacokinetics up to a dose of 15 mg twice daily, with low intersubject variability, after single and multiple doses (Tmax 1 vs. 1.5 h; Cmax 74 vs. 73.6 ng/mL; AUC(0-t) 440 vs. 414 ng·h/mL; t1/2 4.042 vs. 3.566 h). The bioavailability of S-pindolol after equivalent doses of pindolol (20 mg) and ACM-001.1 (10 mg) was comparable, and formal bioequivalence margins were met (90% CI for Cmax, AUC(0-t) and AUC(0-inf) within 80%-125% bioequivalence acceptance criteria). No evidence of stereoconversion of the S-enantiomer into the R-enantiomer, no accumulation, dose linearity and dose proportionality of S-pindolol over a range of doses were demonstrated; we also show indirectly that there was no food effect. ACM-001.1 was generally well tolerated, with no apparent relationship of side effects to dose, no serious adverse events, severe treatment-emergent adverse events (TEAEs) or deaths, and similar incidences of TEAEs (fatigue, dizziness, somnolence, nausea and headache) with ACM-001.1 10 and 15 mg and pindolol 20 mg.ConclusionsData from this bridging study of enantiomerically pure ACM-001.1 and its parent racemic drug, pindolol, support clinical trials of ACM-001.1 for the treatment of cancer cachexia.

Dataset Information

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.

Aims

Methods

Results

Conclusion

Publications

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.

Similar Datasets

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