ADMINISTRATION OF HUMAN RECOMBINANT INSULIN-LIKE GROWTH FACTOR-I TO PATIENTS FOLLOWING MAJOR GASTROINTESTINAL SURGERY

OBJECTIVE The aim was to study the pharmacokinetic parameters and biological activity of a single dose of human recombinant IGF-I (rhIGF-I) administered to patients following major gastrointestinal surgery. DESIGN A double blind placebo controlled externally randomized study of 30 patients; the study commencing 24 hours after major colonic or gastric surgery. MEASUREMENTS After a baseline blood sampling day, IGF-I (40 mug/kg by single subcutaneous dose, n=20) or placebo (n=10) was administered and serum and urine samples collected over the ensuing 72 hours. Serum IGF-I, IGF-II, IGF binding proteins (IGFBP-1, IGFBP-3), GH and insulin were measured by radioimmunoassay. Serum IGF bioactivity was assessed using a validated porcine cartilage bioassay. Serum and urinary electrolytes were measured by standard methodoLogy. RESULTS Serum immunoreactive IGF-I levels peaked at 4 hours following injection of IGF-I (1.09+/-0.12 U/ml mean+/-SEM), remained elevated for 15 hours and returned to basal levels by 24 hours after injection. IGF bioactivity was increased by 57% 6 hours after IGF-I injection. Mean levels of IGFBP-1 and IGFBP-3, IGF-II and GH were unaffected by IGF-I administration. Insulin levels were suppressed at 30 minutes following injection of IGF-I compared with the placebo group (16.9+/-3.0 mU/l vs 32.3+/-71, P=0.02); thereafter, there were no differences in insulin levels. The mean change in serum creatinine following IGF-I (-6.3+/-3.0 mmol/l) was significantly different from that in the control group (+7.2+/-6.2, P=0.03). Creatinine clearance rose from a mean of 71.6+/-7.5 ml/min to 83.2+/-7.6 ml/min after IGF-I treatment (P=0.02). In the IGF treated patients, cholesterol levels consistently fell (-0.20+/-0.05 mmol/l); this was not observed in the placebo group (+0.20+/-0.14, P=0.006). Basal serum potassium levels in the IGF treatment group (4.1+/-0.1 mmol/L) fell to 3.8+/-0.1 at 4 hours (P=0.002) and 3.6+/-0.1 at 10 hours (P=0.001) returning to a level of 4.0+/-0.1 (P=0.293) at 24 hours after injection. There were no other observed differences in serum or urinary electrolytes or serum free fatty acids and triglycerides. Pharmacokinetic parameters derived from baseline adjusted IGF-I measurements revealed a slow absorption of the administered dose with a T(max) of 5.0+/-0.43 hours and an elimination half-life of 10.8+/-1.2 hours. The computed volume of distribution was 0.33+/-0.05 l/kg and the clearance on average 25 ml/min. CONCLUSIONS A single subcutaneous dose of IGF-I normalized circulating IGF-I levels in post-operative patients, was well tolerated and without side-effects. IGF bioactivity was increased and associated with a fall in serum cholesterol, potassium and creatinine levels and a rise in creatinine clearance. Further long-term studies are now required to assess the anabolic effects of rhIGF-I in this type of patient group.