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Pharmacokinetics and Pharmacodynamics of Growth Hormone-Releasing Peptide-2: A Phase I Study in Children¹

Department of Pediatrics, University of Washington (C.P.), Seattle, Washington 98105; the Departments of Pediatrics and Pharmacology, University of Missouri (G.K.), and the Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, Children’s Mercy Hospital (G.K.), Kansas City, Missouri 64108; Wyeth-Ayerst Research (D.F.), Princeton, New Jersey 08543; and the Department of Medicine, Tulane University School of Medicine (C.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Catherine Pihoker, M.D., Division of Pediatric Endocrinology, Children’s Hospital and Medical Center, P.O. Box 5371, CH-92, Seattle, Washington 98105.

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 µg/kg iv 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 E_max model. Disposition of GHRP-2 best fit a biexponential function. GHRP-2 PK parameters (mean ± SD) were: = 13.4 ± 9.7 h^-1, ß = 1.3 ± 0.3 h^-1, t_1/2ß = 0.55 ± 0.14 h, AUC⁰ = 2.02 ± 1.37 ng/mL·h, C_max = 7.4 ± 3.8 ng/mL, plasma clearance = 0.66 ± 0.32 L/h·kg, and apparent volume of distribution = 0.32 ± 0.14 L/kg. PK parameters for GH were: appearance rate constant = 5.9 ± 3.1h^-1, elimination t_1/2 = 0.37 ± 0.15 h, lag time = 0.05 ± 0.01 h, C_max = 50.7 ± 17.2 ng/mL, T_max = 0.42 ± 0.16 h, and AUC⁰ = 47.9 ± 26.1 ng/mL·h. PD parameters for GHRP-2 were: K_e0 = 1.13 ± 0.94 h^-1, = 13.15 ± 9.44, E₀ = 6.63 ± 4.86 ng/mL (GH), E_max = 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.

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