GROWTH HORMONE PHARMACOKINETICS AND ACUTE BIOLOGIC RESPONSES IN CHILDREN WITH CHRONIC RENAL INSUFFICIENCY. • 2160

The pharmacokinetics (PK) of recombinant human growth hormone (rhGH) and the acute biologic response variables insulin-like growth factor I (Total IGF-I), IGF binding protein 3 (IGFBP3), and growth hormone binding protein(GHBP) were evaluated in six, previously untreated, children (4M, 2F; ages 6-11 years) with chronic renal insufficiency (calculated creatinine clearance values 14 to 37 mL/min/1.73m²). Each patient received, in random order, rhGH as a 50 μg/kg IV bolus, rhGH as a 50 μg/kg SC bolus and excipient as a SC bolus. There was a minimum 4 week washout between dosing periods. Serum samples were collected at selected time intervals up to 48 hours postdose and were analyzed for hGH concentrations (ELISA), Total IGF-I (RIA after acid-ethanol extraction), IGFBP3 (RIA), and GHBP (LIFA). PK parameters were estimated by both compartmental and noncompartmental methods. Serum hGH profiles for IV or SC-administered rhGH were very similar for all six patients. Terminal half-lives were 24-44 min and 2.7-3.3 hrs following IV and SC administration, respectively. Following SC administration, GH serum levels returned to non-detectable levels by 16-22 hours postdose and absoluate SC bioavailability was approximately 70%. Mean total systemic clearance (CL/W) was reduced 15-30% compared to normal subjects. The total systemic clearance was approximately proportional to the creatinine clearance for the patients. The biologic response parameters were variable both among patients and dosing periods. No consistent changes in GHBP levels were observed after dosing. Total IGF-I levels increased after both IV and SC dosing of rhGH. The areas under the Total IGF-I response curves (AUC) after SC dosing were 3 to 5-fold larger than after IV dosing. The increase in Total IGF-I occurred in the absence of any consistent increases in IGFBP3 levels. The pharmacokinetic parameters and acute biologic response data obtained in this study support the safety and efficacy of the current dosing regimens for rhGH in chronic renal failure. Funding for this study was provided by Genentech, Inc.