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 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 T1/2 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 Smax = 2.2, SC50 = 6.5 ng/ml, and gamma (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.
Sun
Y N
YN
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, New York, USA.
Lee
H J
HJ
Almon
R R
RR
Jusko
W J
WJ
D000818:Animals; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D013006:Growth Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D007700:Kinetics; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D008863:Microspheres; D008954:Models, Biological; D013997:Time Factors
D003692:Delayed-Action Preparations; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone