Dymphy Huntjens (1), Anne Chain (1), David Spalding (2), Meindert Danhof (1) and Oscar Della Pasqua(1,3)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands (2) GlaxoSmithKline, Drug Metabolism & Pharmacokinetics, United Kingdom (3) GlaxoSmithKline, Clinical Pharmacology & Discovery Medicine, United Kingdom
Objectives: Rofecoxib is a potent and highly selective cyclo-oxygenase-2 inhibitor and is often prescribed for human ailments such as acute pain and osteoarthritis. Previous investigations have demonstrated that the PK of rofecoxib displays enterohepatic recycling (EHC) in rats1. The objective of this study was to develop a population pharmacokinetic (pPK) model for rofecoxib in rats.
Methods: Male rats, instrumented with one or two cannulas, received an IV (6, 10 mg/kg in 5 min, 0.5 mg/kg in 60 min) an IP (10 mg/kg) or a PO (5 mg/kg) dose of rofecoxib. Plasma samples were taken at pre-defined time-points to obtain concentration-time profiles. These profiles displayed large inter- and intra-individual variability and multiple secundary peaks at different time-points. To describe the data, various models were investigated in NONMEM, including EHC models, the Wajima model and constrained longitudinal spline (CLS) models with different breakpoints.
Results: The EHC model and Wajima model were not able to accurately describe the observed concentration-time profiles. A fourth order CLS model with 4 breakpoints best decribed the PK profiles independent of the route of administration. A proportional and additive error model described intra-individual variability. Addition of data of bile duct-cannulated rats enabled the determination of relative bioavailability and thus total exposure in a quantitative manner. EHC resulted in increased bioavailability in normal rats (approximately 150%) as compared to bile duct-cannulated rats.
Conclusions: The CLS method was able to describe the noisy EHC-related fluctuations in plasma concentrations of rofecoxib in rats. A accurate estimation of total exposure is required to estimate the relevance of the increase of EHC in bioavailability.
References:
1Baillie T., Drug Met. & Dis 29, 2001
Reference: PAGE 13 () Abstr 533 [www.page-meeting.org/?abstract=533]
Poster: poster