Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.
OBJECTIVE
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 mIU/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.
Gobburu
J V
JV
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, USA.
Agersø
H
H
Jusko
W J
WJ
Ynddal
L
L
D000328:Adult; D004305:Dose-Response Relationship, Drug; D006728:Hormones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests
D006728:Hormones; D009842:Oligopeptides; D019382:Human Growth Hormone; C114611:ipamorelin