Abstract
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 γ (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.
Footnotes
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Send reprint requests to: William J. Jusko, Ph.D., 565 Hochstetter Hall, Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260. E-mail:wjjusko{at}acsu.buffalo.edu
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↵1 This work was supported by Alkermes, Inc. and by Grants GM 24211 and AG 10629 from the National Institute of General Medical Sciences and the National Institute on Aging, National Institutes of Health.
- Abbreviations:
- rhGH
- recombinant human growth hormone
- IGF-I
- insulin-like growth factor I
- PK/PD
- pharmacokinetics/pharmacodynamics
- AUC
- area under the curve
- AUEC
- area under the effect curve
- CL
- clearance
- Vc, volume of distribution in the central compartment
- Vss, volume of distribution at the steady state
- ka, first-order absorption rate constant
- k12 and k21, distribution rate constants
- λ1 and λ2
- slope coefficients
- kel, elimination rate constant
- F, bioavailability
- s.c.
- subcutaneous
- MRT
- mean residence time
- kin
- IGF-I formation rate
- kout
- IGF-I elimination rate
- Smax
- maximum stimulation of IGF-I formation rate
- SC50
- rhGH concentration producing 50% of the maximum effect
- γ
- slope coefficient for the Hill function
- HX
- hypophysectomized
- GHBP
- growth hormone-binding protein
- Received November 10, 1998.
- Accepted January 28, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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A Pharmacokinetic/Pharmacodynamic Model for Recombinant Human Growth Hormone Effects on Induction of Insulin-Like Growth Factor I in Monkeys
