Growth hormone-releasing activity of hexarelin in humans. A dose-response study
Imbimbo BP, Mant T, Edwards M, Amin D, Dalton N, Boutignon F, Lenaerts V, Wuthrich P, +1 more
European Journal of Clinical Pharmacology (1994) · n=12
Twelve adult male volunteers in a placebo-controlled rising-dose IV study; an ED50 of approximately 0.5 µg/kg, peak plasma GH at 30 minutes, return to baseline by 240 minutes — the foundational human pharmacokinetic and pharmacodynamic characterisation of hexarelin.
This is the foundational human pharmacology paper for hexarelin, published in European Journal of Clinical Pharmacology in 1994 by Imbimbo and colleagues at Mediolanum Farmaceutici (Milan) in collaboration with the Mant clinical-pharmacology unit at Guy's Hospital, London. The paper is the first published human dose-response and PK characterisation of the synthetic hexapeptide (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) that emerged from Romano Deghenghi's medicinal-chemistry programme as the second-generation refinement of the GHRP-6 backbone.
The trial was a randomised, double-blind, placebo-controlled rising-dose study in 12 healthy adult male volunteers. Single intravenous doses of 0.5, 1, and 2 µg/kg were administered in separate sessions, with serial plasma sampling for hexarelin concentration and growth hormone concentration over the four hours following dosing. The headline pharmacodynamic finding is the GH response curve: hexarelin produced dose-dependent increases in plasma GH that peaked at approximately 30 minutes post-dose, with peak concentrations ranging from approximately 3.9 to 55.0 ng/mL across the three doses, returning toward baseline by 240 minutes. The half-maximum effective dose for GH release was approximately 0.5 µg/kg (the 95% confidence interval estimated by the authors was 0.50–0.64 µg/kg), and the 2 µg/kg dose approached the maximal GH response, consistent with the receptor-saturation curve that would later be characterised in detail for the GHSR-1a ghrelin receptor. The pharmacokinetic component established a plasma terminal half-life of approximately 55 minutes after IV administration — the kinetic parameter that grounds the subsequent route-comparison work showing that subcutaneous bioavailability of hexarelin is approximately 77% and that meaningful oral exposure is essentially unachievable.
This paper is the first piece of the hexarelin human pharmacology base and is the methodological template the Deghenghi group used for the subsequent age- and pubertal-stratification studies (Ghigo, Loche, Arvat) through the mid-1990s. The Mediolanum development programme in pediatric GH deficiency that followed from this paper did not reach FDA approval, but the human PK/PD characterisation it established remains the most rigorous published baseline for any GHRP in the class.
This is a small Phase I-style PK/PD study in 12 healthy adult male volunteers — a fit-for-purpose sample size for dose-response characterisation but not generalisable to chronic-dosing pharmacology, female responders, paediatric or geriatric populations, or non-healthy clinical populations. The IV route used here is not the route by which hexarelin has been administered in any subsequent practitioner-protocol context; the route-comparison and bioavailability work in Ghigo et al., JCEM 1994 is the bridge to subcutaneous PK. The 30-minute peak and ~55-minute plasma half-life established here describe the acute pulse signature and do not characterise the receptor-desensitisation phenomenon that emerges with chronic dosing, which Rahim, O'Neill, and Shalet 1998 subsequently documented. The dose-response is reported on the GH endpoint only; the parallel cortisol, prolactin, and ACTH spillover that would later differentiate hexarelin from selective secretagogues like Ipamorelin is not addressed in this paper and emerges in the Massoud 1996 and Arvat 1997 follow-on work. The Mediolanum-affiliated authorship (Boutignon, Lenaerts, Wuthrich, Deghenghi) is disclosed; the work is industry-sponsored Phase I pharmacology and should be read in that context. The /peptides/hexarelin page treats this paper as the load-bearing acute-PK reference and contextualises it within the broader development trajectory that did not produce a marketed indication.
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