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

Abstract

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 Tmax 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.

Trial registration: ClinicalTrials.gov NCT02039349.

Keywords: Phase I; clinical trial; gastric emptying; ghrelin; growth hormone; somnolence.

© 2016 The British Pharmacological Society.

Figures

Figure 1

Heart rate. (A) Single ascending dose (SAD), (B) multiple ascending dose (MAD) showing tachyphylaxis and (C) clinical heart rate variability (HRV). (A) SAD study median heart rate change from baseline (CFB) with lines indicating PF‐05190457 doses (0–300 mg) and panels for divided dose administration (dosed with breakfast, 2 h post breakfast, with dinner, and 2 h post dinner; Cohort 4), fasted (dosed without breakfast; Cohorts 1 and 2), fed (dosed with breakfast; Cohort 2) and gastric emptying examination (dosed 2 h before a stable isotope gastric emptying test meal; Cohort 3). “M” indicates the time of a meal, and arrows from the top of the panel indicate the time of dosing. (B) MAD study heart rate tachyphylaxis. Lines compare the heart rate change from time‐matched baseline (CFB) to Day 1 or 13; panels indicate increasing dose of twice‐daily (BID) PF‐05190457. “M” indicates the time of a meal, and arrows from the top of the panel indicate the time of dosing. (C) HRV) by increasing PF‐05190457 dose in the fasted state during the SAD study Cohorts 1 and 2 with panels for HRV power in a frequency band. Boxes represent the 25th to 75th percentiles of observations; whiskers represent the farthest observation ≤1.5‐times the inter‐quartile range from the top or bottom quartile; closed circles are the median for the treatment and open circles are observations outside the whiskers

Figure 2

Multiple ascending dose study median PF‐05190457 plasma concentrations

Figure 3

Median gastric emptying rate of isotope recovery by time with 150 mg PF‐05 190 457 or placebo from the single ascending dose study Cohort 3

Figure 4

Ghrelin‐induced growth hormone (GH) area under the concentration–time curve during the acyl ghrelin infusion (from 6 to 9.5 h: AUC6–9.5) by treatment and day in the multiple ascending dose study. Note that Cohort 1 had 5 pmol kg–1 min–1 ghrelin infusion while Cohorts 2–4 had 1 pmol kg–1 min–1 ghrelin infusion. One subject in the placebo group had intravenous infiltration during infusion on Day 1 and was omitted from the figure