{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:49:48Z","timestamp":1775980188692,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n S<\/jats:italic>\n \u2010pindolol has metabolic effects of potential benefit in cancer cachexia: reduced catabolism through nonselective \u03b2\u2010blockade; increased anabolism through partial \u03b22 receptor agonism;\u00a0and increased appetite and reduced fatigue through central 5\u2010hydroxytryptamine\/serotonin receptor activity. A Phase 2a clinical trial demonstrated that\n S<\/jats:italic>\n \u2010pindolol can reverse weight loss and improve fat\u2010free mass in patients with cancer\u2010related weight loss. A comparative phase I bioavailability study of\n S<\/jats:italic>\n \u2010pindolol and racemic pindolol was performed to support the development of\n S<\/jats:italic>\n \u2010pindolol in cancer cachexia.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This two\u2010part study assessed the comparative bioavailability and pharmacokinetics of single doses of\n S<\/jats:italic>\n \u2010pindolol benzoate (ACM\u2010001.1) or pindolol (Part 1) and the steady\u2010state pharmacokinetics and pharmacodynamics of multiple doses of ACM\u2010001.1 and pindolol (Part 2) in healthy volunteers (NCT06028321). ACM\u2010001.1 5, 10 and 15\u2009mg and pindolol 15, 20 and 30\u2009mg were tested. In Part 1, subjects were randomised to ACM\u2010001.1 15\u2009mg followed after a 48\u2010h washout period by pindolol 30\u2009mg, or the reverse sequence; another group received pindolol 15\u2009mg. Subjects in Part 2 were randomised to pindolol 20\u2009mg twice\u2010daily or ACM\u2010001.1 5, 10 or 15\u2009mg twice\u2010daily for 4\u2009days. Bioavailability, pharmacokinetics, pharmacodynamics, potential for and extent of stereoconversion, and tolerability were assessed.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Parts 1 and 2 included 24 and 27 healthy volunteers, respectively. ACM\u2010001.1 had predictable pharmacokinetics up to a dose of 15\u2009mg twice daily, with low intersubject variability, after single and multiple doses (\n T<\/jats:italic>\n max<\/jats:sub>\n 1 vs. 1.5\u2009h;\n C<\/jats:italic>\n max<\/jats:sub>\n 74 vs. 73.6\u2009ng\/mL; AUC\n \n (0\u2212\n t<\/jats:italic>\n )\n <\/jats:sub>\n 440 vs. 414\u2009ng\u00b7h\/mL;\n t<\/jats:italic>\n 1\/2<\/jats:sub>\n 4.042 vs. 3.566\u2009h). The bioavailability of\n S<\/jats:italic>\n \u2010pindolol after equivalent doses of pindolol (20\u2009mg) and ACM\u2010001.1 (10\u2009mg) was comparable, and formal bioequivalence margins were met (90% CI for\n C<\/jats:italic>\n max<\/jats:sub>\n , AUC\n \n (0\u2212\n t<\/jats:italic>\n )\n <\/jats:sub>\n and AUC\n (0\u2013inf)<\/jats:sub>\n within 80%\u2013125% bioequivalence acceptance criteria). No evidence of stereoconversion of the\n S<\/jats:italic>\n \u2010enantiomer into the\n R<\/jats:italic>\n \u2010enantiomer, no accumulation, dose linearity and dose proportionality of\n S<\/jats:italic>\n \u2010pindolol over a range of doses were demonstrated; we also show indirectly that there was no food effect. ACM\u2010001.1 was generally well tolerated, with no apparent relationship of side effects to dose, no serious adverse events, severe treatment\u2010emergent adverse events (TEAEs) or deaths, and similar incidences of TEAEs (fatigue, dizziness, somnolence, nausea and headache) with ACM\u2010001.1 10 and 15\u2009mg and pindolol 20\u2009mg.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Data from this bridging study of enantiomerically pure ACM\u2010001.1 and its parent racemic drug, pindolol, support clinical trials of ACM\u2010001.1 for the treatment of cancer cachexia.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13651","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T05:43:04Z","timestamp":1733982184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacokinetics, Pharmacodynamics and Bioavailability of ACM\u2010001.1 (\n S<\/i>\n \u2010Pindolol Benzoate) in Healthy Volunteers"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1366-7958","authenticated-orcid":false,"given":"Frank","family":"Misselwitz","sequence":"first","affiliation":[{"name":"Actimed Therapeutics London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"Henderson","sequence":"additional","affiliation":[{"name":"Quotient Sciences Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Somasekhara\u00a0R.","family":"Menakuru","sequence":"additional","affiliation":[{"name":"Quotient Sciences Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine","family":"Morten","sequence":"additional","affiliation":[{"name":"Actimed Therapeutics London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Roe","sequence":"additional","affiliation":[{"name":"Quotient Sciences Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth","family":"Whitaker","sequence":"additional","affiliation":[{"name":"Quotient Sciences Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Wohlfeil","sequence":"additional","affiliation":[{"name":"Actimed Therapeutics London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"McDermott","sequence":"additional","affiliation":[{"name":"Quotient Sciences Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13539-014-0154-x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13539-012-0087-1"},{"issue":"2","key":"e_1_2_8_4_1","first-page":"187s","article-title":"Pindolol\u2014A Beta\u2010Adrenoceptor Blocking Drug With Partial Agonist Activity: Clinical Pharmacological Considerations","volume":"13","author":"Aellig W. 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