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

Abstract

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. Tables of Links 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...

Drug Therapy in Obesity: A Review of Current and Emerging Treatments

“…However, results in human trials are less favourable with no difference in weight between obese patients receiving ghrelin immunisation over 20 weeks, with both active and control groups losing 3.6 kg weight [92]. We were unable to identify any current clinical trials exploring ghrelin antagonism under progress, though recently ghrelin receptor inverse agonists have been successfully profiled in humans [93].…”

Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism

“…These results suggest that the ghrelin receptor agonist may be used for patients with chronic kidney diseases and symptomatic gastroparesis in the future, but more clinical studies are still needed. In pharmacokinetics and pharmacodynamics of the clinical trial, ghrelin receptor inverse agonists acutely block the ghrelin receptor in healthy volunteers and dose-dependently increase heart rate, delay gastric emptying, and induce somnolence [ 60 ]. Unacylated ghrelin analog is well tolerated in humans and exhibits metabolic benefits in overweight/obese and T2DM subjects [ 61 ].…”

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial

“…Antagonizing or blocking the effects of AG on food intake, body weight and glucose metabolism has emerged in the past decade as an attractive pharmaco-therapeutic target. Antagonists and inverse agonists of the AG receptor GHSR, as well as AG-blocking agents have been designed to this end, but mixed results have been obtained so far in animal models while clinical efficacy data are lacking ([ 26 , 27 ]). On the other hand, inhibitors of the Ghrelin O-Acyltransferase (GOAT) enzyme responsible for acylation are still at an early stage of investigation and no efficacy data is available [ 27 ].…”