Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects.
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 ± 10.4 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.



PF-05190457 absorption was rapid with a Tmaxof 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dose-dependently blocked ghrelin (1 pmol kg-1min-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-1and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks.



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.
Biotherapeutics Clinical Pharmacology, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA.
William S
WS
Denney
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA.
Gabriele E
GE
Sonnenberg
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA.
Santos
S
Carvajal-Gonzalez
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA.
Theresa
T
Tuthill
Cardiovascular, Metabolic, and Endocrine Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, 02139, USA.
V Margaret
VM
Jackson
D000284:Administration, Oral; D000328:Adult; D001384:Azetidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D054314:Drug Inverse Agonism; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D054440:Receptors, Ghrelin / Q000819:agonists*; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D001384:Azetidines; C000606714:PF-5190457; D054440:Receptors, Ghrelin; D013141:Spiro Compounds
Phase I; clinical trial; gastric emptying; ghrelin; growth hormone; somnolence