PHARMACOKINETICS OF RECOMBINANT HUMAN INSULIN-LIKE GROWTH FACTOR-I GIVEN SUBCUTANEOUSLY TO HEALTHY-VOLUNTEERS AND TO PATIENTS WITH GROWTH-HORMONE RECEPTOR DEFICIENCY

The pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) were studied in healthy volunteers and in patients with growth hormone receptor deficiency (GHRD; Laron syndrome). Following single subcutaneous injections of rhIGF-I, 40 and 80 mug/kg, to healthy volunteers, the peptide was absorbed slowly, with a maximum concentration reached after about 7 hours. Following daily multiple subcutaneous injections of rhIGF-I, 40 mug/kg, trough concentrations of IGF-I were increased by 277 +/- 50 mug/l (mean +/- SD) from baseline. IGF-I was thus characterized as a low-clearance peptide, with a clearance and half-life estimated at about 0.20 ml/minute/kg and 20 hours, respectively, in healthy volunteers. The volume of distribution was low, about 0.20-0.36 litres/kg, the bioavailability of subcutaneously administered rhIGF-I was 100%, and the rate of production of IGF-I was estimated to be about 50 mug/kg/day (3.5 mg/day). Patients with GHRD had low baseline IGF-I concentrations (30-50 mug/l) and a much more rapid turnover of IGF-I compared with that in healthy volunteers. The clearance and half-life of IGF-I were estimated to be about 0.60 ml/minute/kg and 6 hours, respectively. The volume of distribution was about the same as in healthy subjects. Due to the rapid turnover of IGF-I, trough IGF-I concentrations were increased to just above baseline during subcutaneous injections of 40 mug/kg once daily for 7 days. The maximum increase in IGF-I levels was 111 +/- 12 mug/l and 150 +/- 3 mug/l following daily subcutaneous injections of 40 x 1 and 40 x 2 mug/kg for 7 days, respectively.