Vol. 289, Issue 3, 1523-1532, June 1999

A Pharmacokinetic/Pharmacodynamic Model for Recombinant Human Growth Hormone Effects on Induction of Insulin-Like Growth Factor I in Monkeys¹

Yu-Nien Sun, Hye Jung Lee, Richard R. Almon and William J. Jusko

Department of Pharmaceutics, School of Pharmacy (Y.-N.S., R.R.A., W.J.J.), and Department of Biological Sciences (R.R.A.), State University of New York at Buffalo, Buffalo, New York; and Alkermes, Inc., Cambridge, Massachusetts (H.J.L.)

The pharmacokinetics of recombinant human growth hormone (rhGH) and its effects on the induction of insulin-like growth factor I (IGF-I) were studied in juvenile rhesus monkeys. Disposition profiles of rhGH from two short-term 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 were included in this study: group A, ProLease rhGH (24 mg), a sustained-release microsphere formulation; group B, a single s.c. injection plus an implanted osmotic pump (24.4 mg); group C, a single s.c. injection (25.9 mg); group 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 pump provided zero-order inputs of rhGH and maintained the serum rhGH concentrations 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/ml, and  (slope coefficient) = 6.8, which were applicable to all treatments. The area under effect curve showed group B to be most effective for IGF-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 given the highest dose. Group D had modest IGF-I induction, but the pulsatile rhGH input is less effective than continuous input provided by ProLease. Our pharmacokinetic/pharmacodynamic model demonstrates that ProLease and osmotic pump delivery were best able to maintain rhGH level above the s.c.₅₀ value, which provided more effective IGF-I induction compared with the single or daily subcutaneous injections in solution.