Pharmacokinetics, Pharmacodynamics and Bioavailability of ACM-001.1 (S-Pindolol Benzoate) in Healthy Volunteers.

BACKGROUND

S-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.

METHODS

This 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.

RESULTS

Parts 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 (T 1 vs. 1.5 h; C 74 vs. 73.6 ng/mL; AUC 440 vs. 414 ng·h/mL; t 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 C, AUC and AUC 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.

CONCLUSIONS

Data 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.