Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys

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 ϭ 18) was conducted, where single doses of 1, 3, and 10 MIU/kg of recombinant-human interferon-␤ (IFN-␤) 1a were given i.v. and then s.c. Plasma concentrations of IFN-␤ 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 ϭ 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 (T max ϭ 3 h) and incomplete bioavailability (F ϭ 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 S max ϭ 23.8. Greater relative neopterin response after s.c. dosing was accounted for by prolonged receptor activation relative to the SC 50 value. Repeated daily s.c. dosing produced modestly elevated IFN-␤1a 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 S max and receptors. The PK/PD model for IFN-␤1a 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.The interferons (IFNs) represent a family of endogenous proteins that exhibit antiviral, antiproliferative, and immunomodulatory effects (Pestka et al., 1987;Leonard, 1999). These compounds are being investigated for a variety of clinical indications. IFN-␤, in particular, has shown dosedependent efficacy in several clinical trials and is being used for treatment of multiple sclerosis (for review, see Goodin et al., 2002). The mechanism of action for this indication is still unclear and is likely that the activity is due to a combination of some of the biological activities of IFN-␤ (Yong et al., 1998), including antiviral activity, changes in cell distribution, activation of cytotoxic activities of lymphocytes, macrophages, and natural killer cells, regulation of cytokine and cytokine receptor gene expression, and an increase in expression of some tumor-associated antigens (Pestka et al., 1987;Leonard, 1999).Limited analyses of the pharmacokinetics/pharmacodynamics (PK/PD) of IFN-␤ have been reported. In general, plasma concentrations of IFN-␤ decline rapidly in a biexponential manner after i.v. administration, with a terminal half-life of approximately 5 h in humans (Wills, 1990;Chiang et al., 1993;Salmon et al., 1996). After s.c. or i.m. dosing, ...

Diversity of Mechanism-Based Pharmacodynamic Models

“…A third example of a complex PK/PD model is for the target-mediated PK/PD of interferon-␤1a. Components of receptor binding, a precursor indirect response model, and two mechanisms of tolerance were needed to explain the effects of this agent on neopterin dynamics in humans and monkeys (Mager and Jusko, 2002). Complex PD models of the general form depicted in Fig.…”

Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

“…The kinetic characteristics of rHuEPO include nonlinear PK, prolonged absorption, and variable incomplete bioavailability on s.c. administration, which has often been observed for other therapeutic protein drugs (Radwanski et al, 1998;Mager and Jusko, 2002) and can be a challenge in assessment of the allometry. In the presence of nonlinear kinetics, direct comparisons of PK parameters of interest such as CL, volume of distribution, and bioavailability are difficult because these values change with dose when calculated by traditional methods.…”

Simultaneous Modeling of Abciximab Plasma Concentrations and ex Vivo Pharmacodynamics in Patients Undergoing Coronary Angioplasty

“…Abciximab also represents a high-affinity binding agent with similar receptorbinding/pharmacodynamic relationships and a shared antagonistic mechanism of action. This is in contrast to potential target-mediated drugs that act through agonistic mechanisms and have been modeled using the drug-target complex to drive the pharmacological effect (Kang and Weiss, 2002;Mager et al, 2003). Furthermore, this complex PK/PD behavior of abciximab may in fact correspond with a significant therapeutic advantage.…”