PHARMACOKINETICS AND PHARMACODYNAMICS OF GROWTH HORMONE-RELEASING PEPTIDE-2 - A PHASE-I STUDY IN CHILDREN

Administration of GH-releasing peptide-2 (GHRP-2) represents a potenti al mode of therapy for children of short stature with inadequate secre tion of GH. Requisite information to determine the dosing route and fr equency for GHRP-2 consists of the pharmacokinetics (PK) and pharmacod ynamics (PD) for this compound, neither of which. have been previously evaluated in children. The purpose of this study nias to characterize the PK and PD of GHRP-2 in children with short stature. Ten prepubert al children (nine boys and one girl; 7.7 +/- 2.4 yr old) received a si ngle 1 mu g/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 specifi c RIA methods. PK parameters were calculated from curve fitting of GHR P-2 and GK vs. time data. Posttreatment plasma GH concentrations (norm alized for pretreatment values) were used as the effect measurement. P ID parameters were generated using the sigmoid E-max model. Dispositio n of GHRP-2 best lit a biexponential function. GHRP-2 PK parameters (m ean +/- SD) were: alpha = 13.4 +/- 9.7 h(-1), beta = 1.3 +/- 0.3 h(-1) , t(1/2 beta) = 0.55 +/- 0.14 h, AUC(0-->infinity) = 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 parame ters for GH were: appearance rate constant = 5.9 +/- 3.1h(-1) eliminat ion t(1/2) = 0.37 +/- 0.15 h, lag time = 0.05 +/- 0.01 h, C-max = 50.1 +/- 17.2 ng/mL, T-max = 0.42 +/- 0.16 h, and AUC(0-->infinity) = 47.9 +/- 26.1 ng/mL.h. PD parameters for GHRP-2 were: K-eo = 1.13 +/- 0.94 h(-1), gamma = 13.15 +/- 9.44, E-0 = 6.63 +/- 4.86 ng/mL (GH), E-max = 67.5 +/- 23.5 ng/mL (GR), and EC50 = 1.09 +/- 0.59 ng/mL. We conclud ed that 1) GHRP-2 produced a predictable and significant (i.e. compare d 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 ena ble PD and PK evaluations of extravascular dosing regimens for childre n.