4.2 Article

Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

期刊

PITUITARY
卷 25, 期 2, 页码 328-339

出版社

SPRINGER
DOI: 10.1007/s11102-021-01201-z

关键词

Paltusotine; Acromegaly; IGF-1; SST2; Somatostatin receptor agonist

资金

  1. Crinetics Pharmaceuticals, Inc.
  2. Small Business Innovation Research grant from the National Institutes of Health [R44DK088501]

向作者/读者索取更多资源

This study evaluated the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable nonpeptide agonist for somatostatin receptor subtype 2 (SST2), for the treatment of acromegaly and neuroendocrine tumors. The results showed that paltusotine suppressed growth hormone (GH) and insulin-like growth factor 1 (IGF-1) release in a dose-dependent manner and had a safety profile similar to approved SST2 receptor ligands.
Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (x 7 days), 10, 20, and 30 mg (x 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors.

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