Abstract
A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to simultaneously characterize interferon after i.v. and s.c. dosing at various dose levels. A sequential study in monkeys (n = 18) was conducted, where single doses of 1, 3, and 10 MIU/kg of recombinant-human interferon-β (IFN-β) 1a were given i.v. and then s.c. Plasma concentrations of IFN-β were determined and biphasic neopterin concentrations were used as the pharmacodynamic (PD) endpoint. Multiple dosing also was evaluated by giving 1 MIU/kg s.c. doses once daily for 7 days (n = 3). The integrated model uses target-mediated drug disposition to describe drug elimination by receptor binding and internalization, and well characterizes the observed nonlinear pharmacokinetic (PK) profiles. The s.c. doses exhibited an absorption phase (Tmax = 3 h) and incomplete bioavailability (F = 0.3–0.7). An indirect response model for stimulation of neopterin triphosphate production by activated receptor complex followed by conversion to neopterin was used to jointly model the formation and loss of neopterin with a capacity factor Smax = 23.8. Greater relative neopterin response after s.c. dosing was accounted for by prolonged receptor activation relative to the SC50 value. Repeated daily s.c. dosing produced modestly elevated IFN-β1a concentrations and neopterin concentrations that were lower than simulated from single-dose modeling. Although several mechanisms could be involved, these phenomena were simply remodeled as down-regulation of Smax and receptors. The PK/PD model for IFN-β1a depicts receptor binding as a key feature controlling nonlinear elimination, nonstationary kinetics, and neopterin induction in a manner consistent with known processes controlling its disposition and pharmacological effects.
Footnotes
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This research was supported by Serono International and by Grant GM57980 (to W.J.J.) from the National Institutes of Health. Preliminary results were presented at the American Association of Pharmaceutical Scientists Pharmaceutical Congress of the Americas, Orlando, FL, March, 2001.
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DOI: 10.1124/jpet.103.049502.
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ABBREVIATIONS: IFN, interferon; PK, pharmacokinetics; PD, pharmacodynamics; CV%, coefficient of variation percent; AL, amount of drug in lymphatic compartment; AUC, area under plasma drug concentration-time curve; AUMC, area under the first moment curve; C0 or Cmax, maximum plasma drug concentration; CL, total systemic drug clearance; DR*, amount of internalized drug-receptor complex; DR, amount of drug-receptor complex at cell surface; Dsci, ith s.c. dose level; Fi, bioavailability of the ith s.c. dose level; MIU, million IU; MRT, mean residence time; Vss, steady-state volume of distribution.
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↵1 Current address: Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore, MD 21224.
- Received January 23, 2003.
- Accepted March 18, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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