Sy SK(1,2,3), Pieniaszek HJ(3,4), Kornhauser DM(3), Davidson AF(3), Jiao Q(3), Cain V(3,5), Martin DE(3,6)
1 Innaphase Corporation, Philadelphia, Pennsylvania, USA; 2 Center for Nonlinear Dynamics, Physiology, McGill University, Montreal, Quebec, Canada; 3 Bristol-Myers Squibb, Lawrenceville, New Jersey, USA; 4 HPP Consulting, Newark, Delaware, USA; 5 AstraZeneca, Newark, Delaware, USA; 6 Panacos Pharmaceuticals, Gaithersburg, Maryland, USA
Objective: To investigate the cytochrome P450-modulated effects on the pharmacokinetics and pharmacodynamics of the active hydrolysis metabolite of roxifiban, XV459, through administration of ketoconazole, a potent CYP3A4 inhibitor, and rifampin, a non-specific inducer of CYP3A4. Since the biotransformation of roxifiban was thought to be solely mediated via ester hydrolysis forming XV459, the effect of induction and inhibition of CYP was initially hypothesized not to affect XV459 pharmacokinetics.
Methods: In a randomized, 3-way crossover study, a total of 6 healthy volunteers and 6 subjects with mild renal impairment received 1 mg roxifiban per day for seven days, either alone or in combination with 200 mg ketoconazole once-daily (administered 3 hours before roxifiban for 8 days) or 600 mg rifampin once-daily (administered 3 days before roxifiban for 8 days). Plasma pharmacokinetics of XV459 were assessed using steady-state non-compartmental method in the three treatment groups. Pharmacodynamic response was evaluated using percent inhibition of platelet aggregation and this response was correlated with pharmacokinetic concentrations using a mixed effect nonlinear regression model with creatinine clearance as a covariate of the model. Both model-independent analysis and population pharmacodynamic model were evaluated using Kinetica 4.1.
Results: Ketoconazole significantly decreased XV459 clearance by approximately 36% and 30% and increased the percentage inhibition of platelet aggregation from pretreatment baseline by 30% and 12% in both normal healthy volunteers and mild renally impaired subjects, respectively. CYP inhibition by ketoconazole also shifted the concentration-effect relationship towards increased EC50 by approximately 21%. Concomitant rifampin administration with roxifiban, on the other hand, increased the clearance of XV459 by 91% to 116% resulting in decreased XV459 systemic exposure by 45% and decreased antiplatelet activity by 8% to 21%. CYP induction by rifampin decreased EC50 by approximately 61%.
Conclusion: Concomitant administration of roxifiban with rifampin or ketoconazole produced unexpected changes in the pharmacokinetics of XV459 and significant alterations in antiplatelet activity. The population pharmacodynamic Emax model in Kinetica 4.1 provides a sensitive tool to detect such interaction.
Reference: PAGE 12 (2003) Abstr 453 [www.page-meeting.org/?abstract=453]
Poster: poster