AIMTo evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults.
METHODSSingle (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.
RESULTSPF-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 dosedependently 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.
CONCLUSIONSPF-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.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• PF-05190457 is a selective inverse agonist of the ghrelin receptor with a nonclinical profile supporting human dosing.• Endogenous ghrelin and exogenous infusions in healthy subjects release growth hormone, stimulate hunger and increases gastric motility
WHAT THIS STUDY ADDS• PF-05190457 is the first reported ghrelin receptor inverse agonist profiled in humans. It is safe and well-tolerated in healthy subjects with pharmacokinetics supporting daily oral dosing.• PF-05190457 blocks ghrelin receptors in healthy subjects, dose-dependently increases heart rate, delays gastric emptying, induces somnolence and maximal inhibition for 2 weeks yields tachyphylaxis.
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IntroductionGhrelin is an endogenous 28-amino acid acylated peptide synthesised within the stomach fundus associated with modulating growth hormone secretion, gastric motility, gastric acid secretion and hunger. Acylated ghrelin is the only peripheral hunger-stimulating hormone that elevates preprandially in plasma, suggesting a role in meal initiation in humans [3]. Circulating endogenous baseline and pulsatile patterns of total ghrelin are inhibited in obese subjects following gastric bypass surgery [4,5]; however, not all studies ha...