Effect of Food on the Pharmacokinetics and Pharmacodynamics of an Oral Ghrelin Agonist (ARD‐07) in Healthy Subjects

Abstract

ARD-07 (also known as EP01572) is a peptidomimetic growth hormone secretagogue that can be administered orally. The primary objective of this study is to determine the effects of a meal on the oral bioavailability of ARD-07 after a single oral dose (0.5 mg/kg). In addition, the pharmacodynamic effects (growth hormone release, insulin-like growth factor-1 concentrations) and the tolerability of ARD-07 are investigated in this open-label, randomized, crossover study. Sixteen healthy subjects (8 males, 8 females) receive ARD-07 on 2 different days; the treatment consists of a single oral dose of ARD-07 (0.5 mg/kg body weight), once with and the second day without a test meal. Plasma kinetics of ARD-07 and pharmacodynamic effects are quantified by specific assays. Results are given as mean +/- SEM: The area under the curve for 0 to 24 hours is approximately twice as high without food (27.8 +/- 4.1) than with food (13.7 +/- 1.2; P = .002). The maximum observed ARD-07 concentration relative to dose administration (C(max)) is more than twice as high without food (10.6 +/- 1.6 ng/mL) than with food (4.4 +/- 0.5 ng/mL; P = .001). C(max) of growth hormone occurs at a significantly (P = .001) later stage with food (C(max) = 13.0 +/- 3.5 ng/mL) than without food (37.1 +/- 5.3 ng/mL). Food has a marked effect on the absorption of ARD-07: there is a significant difference in bioavailability between administration of oral ARD-07 with and without food.

Ghrelin: An emerging new anticonvulsant neuropeptide

“…In human plasma, acylated ghrelin was found to disappear more quickly than total ghrelin, with elimination half‐lives of 9–13 and 27–31 min, respectively (Akamizu et al., 2004). A number of synthetic ghrelin agonists are currently being investigated, with compounds such as ARD‐07 (EP01572) showing a promising pharmacokinetic profile with regard to its significantly longer elimination half‐life and good tolerability in human subjects (Piccoli et al., 2007; MacLean et al., 2009).…”

Orally Administered Glucagon-Like Peptide-1 Affects Glucose Homeostasis Following an Oral Glucose Tolerance Test in Healthy Male Subjects

“…The short half–life is a major hurdle; also, the bioavailability of peptides can be reduced by food interactions. Food has recently been shown to markedly reduce the absorption of an orally available ghrelin agonist 28 . To overcome these problems for GLP–1, different strategies are possible.…”

“…Food has recently been shown to markedly reduce the absorption of an orally available ghrelin agonist. 28 To overcome these problems for GLP-1, different strategies are possible. To deal with the short half-life, two classes of pharmaceutical agents have been developed: (i) longacting analogs (GLP-1 mimetics) and (ii) dipeptidyl peptidase IV inhibitors (incretin enhancers).…”

Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia

“…Clinical studies using GHS have shown positive effects on appetite, body weight and body composition in healthy volunteers and in patients with cancer cachexia 12–18 and one such drug, anamorelin, has been recently approved for cachexia treatment in Japan 19 . Macimorelin, a novel, orally active GHS with similar GHSR‐1a binding affinity as ghrelin, is well‐tolerated as a single dose in healthy volunteers and individuals at risk for pituitary dysfunction 9,14,20–28 . It received approval from the US Food and Drug Administration (FDA) in 2017 and European Medicines Agency (EMA) in 2019 as a single dose for adult GH deficiency (AGHD) diagnosis 9,22,29 but has not been examined in repeated doses or in the cancer setting.…”