Article date: February 2017
By: William S. Denney, Gabriele E. Sonnenberg, Santos Carvajal‐Gonzalez, Theresa Tuthill, V. Margaret Jackson in Volume 83, Issue 2, pages 326-338
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 Tmax 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.
DOI: 10.1111/bcp.13127
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