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

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.