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Pharmacokinetics and pharmacodynamics of PF‐05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects
Author(s) -
Denney William S.,
Sonnenberg Gabriele E.,
CarvajalGonzalez Santos,
Tuthill Theresa,
Jackson V. Margaret
Publication year - 2017
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13127
Subject(s) - medicine , pharmacokinetics , placebo , postprandial , tolerability , pharmacodynamics , endocrinology , adverse effect , gastric emptying , insulin , stomach , alternative medicine , pathology
Aim To evaluate safety, tolerability and pharmacokinetics of oral PF‐05190457, an oral ghrelin receptor inverse agonist, in healthy adults. Methods Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo‐controlled, double‐blind studies. Thirty‐five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m –2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF‐05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m –2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF‐05190457 and/or placebo daily for 2 weeks. Results PF‐05190457 absorption was rapid with a T max of 0.5–3 hours and a half‐life between 8.2–9.8 hours. PF‐05190457 dose‐dependently blocked ghrelin (1 pmol kg –1 min –1 )‐induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63–85%] inhibition at 100 mg. PF‐05190457 (150 mg) delayed gastric emptying lag time by 30% [7–58%] and half emptying time by 20% [7–35%] with a corresponding decrease in postprandial glucose by 9 mg dL –1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF‐05190457 plasma concentrations also increased heart rate up to 13.4 [4.8–58.2] beats min –1 and, similar to the effect on glucose and ghrelin‐induced GH, was lost within 2 weeks. Conclusions PF‐05190457 is a well‐tolerated first‐in‐class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin‐induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF‐051940457 has the potential to treat centrally‐acting disorders such as insomnia.