Project Description

Ipamorelin

Starting with the compound NNC 26-0194 [3-(4-imidazolyl) propionyl-D-Phe-Ala-Trp-D-Phe (CH2NH) Lys-ol], Novo Nordisk researchers have developed NNC 26-0161 (ipamorelin)1. Ipamorelin is able to induce a massive release of GH, being active by the intravenous (i.v.), intra-muscular, subcutaneous and oral routes and, interestingly, also by the iontophoresis transdermal route2.

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Ipamorelin exhibits linear pharmokinetics.

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This GH-releasing peptide has a terminal half-life of at least 2 hours with a systemic clearance of .078 L/h/kg and a steady-state volume distribution of .22 L/kg in a typical subject. A large molecule such as a peptide is primarily localized in the central compartment and thus a small volume distribution is expected.3

GHRP-2 in short prepubertal children also produced a small volume distribution (0.32 L/kg) and a half-life of 1.5 hours. 4

Ipamorelin has a 25% longer half-life then GHRP-2.

Ipamorelin’s effect on GH

GH concentrations rise to a sharp peak around .67 hours and decline to very low concentrations in all dosing levels by hour 6. The GH peak concentration levels occur after Ipamorelin peak concentration levels. The plasma Ipamorelin concentration level persisted for longer duration then GH plasma concentration levels and continued to exert an effect on smaller pulses.3

References:

1 – Rasmussen, M.H., Sogaard, B., Ynddal, L., Groes, L., Helmgaard, L. and Nordholm, L. (1998) Ipamorelin – a very potent novel growth hormone secretagogue. Proceedings of 80th Annual Meeting Endocrine Society, New Orleans, USA. Abstr P1-185

2 – Brosnan-Cook, M. et al. (1998) Iontophoretic delivery of ipamorelin, a growth hormone secretagogue. Proceedings of 80th Annual Meeting Endocrine Society, New Orleans, USA. Abstr P1-186

3 – Pharmacokinetic-Pharmacodynamic Modeling of Ipamorelin, a Growth Hormone Releasing Peptide in Human Volunteers, Jogarao V S Gobburu; Henrik Agerso; William J Jusko; Lars Ynddal Pharmaceutical Research; Sep 1999; 16, 9; ProQuest Nursing & Allied Health Source pg. 1412

4 – Pharmacokinetics and Pharmacodynamics of Growth Hormone-Releasing Peptide-2: A Phase I Study in Children1
Catherine Pihoker, Gregory L. Kearns, Daniel French and Cyril Y. Bowers, The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 4 1168-1172

Lets take a look at the Rasmussen 1 in Growth Hormone & IGF Research Volume 8, Issue 4, August 1998, Page 332

P-11 IPAMORELIN – A NOVEL VERY POTENT GROWTH HORMONE SECRETAGOGUE

MH Rasmussen, B Soogaar, L YnddaI, L Groes, L Helmgaard, L Nordholm. Novo Nordisk A/S, Clinical Development, Bagsvaerd, Denmark.

In a randomized, double-blind, placebo-controlled, parallel group, dose-escalation, single-dose trial the pharmacokinetics and the growth hormone (GH) release of ipamorelin a novel pentapeptide GH secretagogue was investigated. Eight healthy male volunteers (6 active, 2 placebo) on each of five dose levels received trial product as a 15 min i.v. infusion. Dose level 1-5: 0.003, 0.01, 0.03, 0.06, 0.1 mg/kg, respectively.

A 10-h plasma profile of ipamorelin was determined for dose level 1-3 and a 24-h plasma profile was determined for dose level 4 and 5. A 10- h plasma profile of GH release was determined for all dose levels. No serious adverse events were reported and none of the subjects withdrew due to an adverse event.

Cmax and AUC for ipamorelin increased with increasing dose ranging from 30-809 nmol/l, and 68-1823 nmol*h/l, respectively. The elimination half-life ranged from 2.4 to 3.1 h for the three lowest dose levels and was 6.4 and 5.5 h for dose level 4 and 5.

Wow!! At high dose Ipamorelin continues to remain active for 5 to more then 6 hours. This means a dose of about 4mgs will result in Ipamorelin in plasma exerting an effect for 5 or so hours.

The latter indicates a deep compartment only revealed after the extended sampling interval or only revealed after high doses. Ipamorelin was able to stimulate GH release in a dose-dependent manner with Cmax ranging from 20-223 mU/l and AUC ranging from 30-373 mU*h/l. This should be compared with a Cmax mean GH value of 11 mU/1 for subjects receiving placebo.

Substantial GH release.

Although linearity between ipamorelin and GH with respect to AUC and Cmax was demonstrated, the maximum concentration of GH was reached in the 0.06 mg/kg dose level, indicating 0.06 mg/kg as the highest effective dose. In conclusion, ipamorelin is able to induce a massive GH release in healthy male subjects.

So the maximum effective Ipamorelin dose (sans GHRH) is 0.06 mg/kg or about 4.8mgs.

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