A pharmacokinetic pharmacodynamic model for recombinant human growth hormone effects on induction of insulin-like growth factor I in monkeys

The pharmacokinetics of recombinant human growth hormone (rhGH) and its eff ects on the induction of insulin-like growth factor I (IGF-I) were studied in juvenile rhesus monkeys. Disposition profiles of rhGH from two short-ter m i.v. infusion studies were described by a two-compartment model yielding a clearance of 16.1 ml/min and T-1/2 of 2.0 h. Four rhGH treatment groups w ere included in this study: group A, ProLease rhGH (24 mg), a sustained-rel ease microsphere formulation; group B, a single s.c. injection plus an impl anted osmotic pump (24.4 mg); group C, a single s.c. injection (25.9 mg); g roup D, daily 0.86-mg s.c. injection for 28 days. Their rhGH input profiles were analyzed by a numerical deconvolution method. ProLease and osmotic pu mp provided zero-order inputs of rhGH and maintained the serum rhGH concent rations around 9 to 13 ng/ml for 16 (group A) and 30 days (group B), For s. c. injections, rhGH underwent first-order absorption. An indirect response model was applied based on use of a Hill function for stimulation of IGF-I production. Parameter values obtained included S-max = 2.2, SC50 = 6.5 ng/m l, and gamma (slope coefficient) = 6.8, which were applicable to all treatm ents. The area under effect curve showed group B to be most effective for I GF-I induction, whereas group A produced the highest peak level in 16 days. Group C had the lowest induction among the four groups, despite being give n the highest dose. Group D had modest IGF-I induction, but the pulsatile r hGH input is less effective than continuous input provided by ProLease. Our pharmacokinetic/pharmacodynamjc model demonstrates that ProLease and osmot ic pump delivery were best able to maintain rhGH level above the s.c.(50) v alue, which provided more effective IGF-I induction compared with the singl e or daily subcutaneous injections in solution.