title: Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children.
abstract: Administration of GH-releasing peptide-2 (GHRP-2) represents a potential mode of therapy for children of short stature with inadequate secretion of GH. Requisite information to determine the dosing route and frequency for GHRP-2 consists of the pharmacokinetics (PK) and pharmacodynamics (PD) for this compound, neither of which have been previously evaluated in children. The purpose of this study was to characterize the PK and PD of GHRP-2 in children with short stature. Ten prepubertal children (nine boys and one girl; 7.7 +/- 2.4 yr old) received a single 1 microg/kg i.v. dose of GHRP-2 over 1 min, followed by repeated (n = 9) blood sampling over 2 h. GHRP-2 and GH were quantitated by specific RIA methods. PK parameters were calculated from curve fitting of GHRP-2 and GH vs. time data. Posttreatment plasma GH concentrations (normalized for pretreatment values) were used as the effect measurement. PD parameters were generated using the sigmoid Emax model. Disposition of GHRP-2 best fit a biexponential function. GHRP-2 PK parameters (mean +/- SD) were: alpha = 13.4 +/- 9.7 h(-1), beta = 1.3 +/- 0.3 h(-1), t(1/2beta) = 0.55 +/- 0.14 h, AUC(0-infinity) = 2.02 +/- 1.37 ng/mL x h, Cmax = 7.4 +/- 3.8 ng/mL, plasma clearance = 0.66 +/- 0.32 L/h x kg, and apparent volume of distribution = 0.32 +/- 0.14 L/kg. PK parameters for GH were: appearance rate constant = 5.9 +/- 3.1 h(-1), elimination t(1/2) = 0.37 +/- 0.15 h, lag time = 0.05 +/- 0.01 h, Cmax = 50.7 +/- 17.2 ng/mL, Tmax = 0.42 +/- 0.16 h, and AUC(0-infinity) = 47.9 +/- 26.1 ng/mL x h. PD parameters for GHRP-2 were: Ke0 = 1.13 +/- 0.94 h(-1), gamma = 13.15 +/- 9.44, E0 = 6.63 +/- 4.86 ng/mL (GH), Emax = 67.5 +/- 23.5 ng/mL (GH), and EC50 = 1.09 +/- 0.59 ng/mL. We concluded that 1) GHRP-2 produced a predictable and significant (i.e. compared to pretreatment values) increase in plasma GH concentrations; 2) the PK-PD link model enabled quantitative assessment of GHRP-2 modulation of serum GH levels; and 3) definition of the EC50 for GHRP-2 will enable PD and PK evaluations of extravascular dosing regimens for children.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle 98105, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pihoker
authors.forename: G L
authors.initials: GL
authors.lastname: Kearns
authors.forename: D
authors.initials: D
authors.lastname: French
authors.forename: C Y
authors.initials: CY
authors.lastname: Bowers
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D006130:Growth Disorders / Q000188:drug therapy* / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000493:pharmacokinetics / Q000494:pharmacology*; D006728:Hormones / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D006728:Hormones; D009842:Oligopeptides; D013007:Growth Hormone-Releasing Hormone; C091874:growth hormone-releasing peptide-2