Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects.

Abstract

To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2±10.4years; body mass index 24.8±3.1kgm-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±10.1years; body mass index 25.9±3.3kgm-2 ) received ≥1 dose (2, 10, 40 and 100mg twice daily) of PF-05190457 and/or placebo daily for 2weeks. PF-05190457 absorption was rapid with a Tmax of 0.5-3hours and a half-life between 8.2-9.8hours. PF-05190457 dose-dependently blocked ghrelin (1pmolkg-1 min-1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100mg. PF-05190457 (150mg) 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 9mgdL-1 . The most frequent adverse event reported by 30 subjects at doses ≥50mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beatsmin-1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2weeks. 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.