Purpose. To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers.
Methods. A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured.
Results. The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin−GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC50) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mlU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters.
Conclusions. The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
B. M. Lippe and J. M. Nakamoto. Conventional and nonconventional uses of growth hormone. Recent Prog. Horm. Res. 48:179-235 (1993).
K. K. Ho, A. J. O'Sullivan, and D. M. Hoffman. Metabolic actions of growth hormone in man. Endocr. J. 43:S57-63 (1996).
M. Oyarzabal, M. Aliaga, M. Chueca, G. Echarte, and A. Ulied. Multicentre survey on compliance with growth hormone therapy: what can be improved? Acta. Paediatr. 87:387-391 (1998).
C. Pintor, S. Loche, R. Puggioni, S. G. Cella, V. Locatelli, A. Lampis, and E. E. Muller. Growth hormone deficiency states: approach by CNS-acting compounds. In Advances in Growth Hormone and Growth Factor Research, eds. E.E. Muller, D. Cocchi, and V. Locatelli, pp. 375-388, Pythogora press, Springer-Verlag, Berlin-Heidelberg, Germany (1989).
C. Y. Bowers. GH releasing peptides-structure and kinetics. J. Pediatr. Endocrinol. 6:21-31 (1993).
M. Ankersen, N. L. Johansen, K. Madsen, B. S. Hansen, K. Raun, K. K. Nielsen, H. Thogersen, T. K. Hansen, B. Peschke, J. Lau, B. F. Lundt, and P. H. Andersen. A new series of highly potent growth hormone-releasing peptides derived from ipamorelin. J. Med. Chem. 41:3699-3704 (1998).
R. Smith; L. H. T. Van der Ploeg, A. D. Howard, S. D. Feighner, K. Cheng, G. J. Hickey, M. J. Wyvratt, M. H. Fisher, R. P. Nargund, and A. A. Patchett. Peptidomimetic regulation of growth hormone secretion. Endocrinol. Rev. 5:621-645 (1997).
C. Y. Bowers, G. A. Reynolds, D. Durham, C. M. Barrera, S. S. Pezzoli, and M. O. Thorner. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J. Clin. Endocrinol. Metab. 70:975-982 (1990).
P. B. Johansen, K. T. Hansen, J. V. Andersen, and N. L. Johansen. Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption. Xenobiotica 28:1083-1092 (1998).
S. L. Beal, L. B. Sheiner, editors. NONMEM user's guide. San Francisco, CA: NONMEM Project Group, University of California; 1992.
N. L. Dayneka, V. Garg, and W. J. Jusko. Comparison of four basic models of indirect pharmacodynamic responses, J. Pharmacokin. Biopharm. 24:457-478 (1993).
C. Pihoker, G. L. Kearns, D. French, and C. Y. Bowers. Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: A phase I study in children. J. Clin. Endocrinol. Metab. 83:1168-1172 (1998).
S. S. Hong, P. Veng-Pedersen, H. Agersoe, and L. Yndal. Semiparametric pharmacodynamic (PD) modeling of biocompound stimulation drugs. PD of a new human growth hormone releasing peptide (GHR). Pharm. Sci. Suppl. 1:S-236 (1998).
K. Friend, A. Iranmanesh, and J. D. Veldhuis. The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days. J. Clin. Endocrinol. Metab. 81:3746-3753 (1996).
J. D. Veldhuis, M. L. Carlson, and M. L. Johnson. The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc. Natl. Acad. Sci. USA 84:7686-7690 (1987).
W. K. DeBell, S. S. Pezzoli, and M. O. Thorner. Growth hormone (GH) secretion during continuous infusion of GH-releasing peptide: partial response attenuation. J. Clin. Endocrinol. Metab. 72:1312-1316 (1991).
K. Raun, B. S. Hansen, N. L. Johansen, H. Thogersen, K. Madsen, M. Ankersen, and P. H. Andersen. Ipamorelin, the first selective growth hormone secretagogue. Eur. J. Endocrin. 139:552-561 (1998).
About this article
Cite this article
Gobburu, J.V.S., Agersø, H., Jusko, W.J. et al. Pharmacokinetic-Pharmacodynamic Modeling of Ipamorelin, a Growth Hormone Releasing Peptide, in Human Volunteers. Pharm Res 16, 1412–1416 (1999). https://doi.org/10.1023/A:1018955126402
- growth hormone releasing peptide (GHRP)
- population pharmacokinetics/pharmacodynamics
- indirect response model