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

Abstract

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.