Lack of Interaction between Modified-Release Fluvastatin and Amlodipine in Healthy Subjects.

OBJECTIVE

To investigate the potential for a pharmacokinetic interaction between fluvastatin modified-release 80mg tablet (Lescol((R)) XL; fluvastatin XL) and amlodipine 5mg tablet (Norvasc((R))) following multiple once-a-day doses for 2 weeks.

DESIGN

This was a single-centre, six-sequence, three-period, randomised, crossover design study. Fluvastatin XL 80mg tablet and amlodipine 5mg tablet were administered once a day for 2 weeks either alone or in combination. Fluvastatin and amlodipine serum concentration profiles were characterised on day 14 for each treatment. The pharmacokinetic interaction between the two drugs was evaluated based on the p-values and 90% confidence intervals (CIs) for log-transformed highest observed concentration (C(max)), area under the plasma concentration-time curve calculated by the linear trapezoidal method up to 24 hours (AUC(24)), and apparent oral clearance at steady state (CL/F), using a single entity as the reference treatment and the combination as the test treatment. Adverse events (AEs), safety laboratory tests and physical examinations were evaluated for safety.

STUDY PARTICIPANTS

Twenty-four healthy subjects were enrolled and 19 completed the study. The safety analysis was based on data from all 24 subjects who received at least one dose of a treatment, while the pharmacokinetic analysis was based on data from the 19 subjects who completed all treatments.

RESULTS

The coadministration of fluvastatin XL and amlodipine resulted in no significant changes in the steady-state AUC (469 vs 454 mug . h/L), C(max) (96 vs 89 mug/L), and CL/F (197 vs 232 L/h) of fluvastatin when compared with fluvastatin XL alone. The p-values for these comparisons were between 0.172 and 0.238, and the 90% CIs for the geometric means were within 78% and 139%. A similar comparison for amlodipine showed no significant difference in the steady-state AUC (132 vs 140 mug . h/L), C(max) (7.1 vs 7.5 mug/L) and CL/F (41 vs 40 L/h) of amlodipine. The p-values for these comparisons were between 0.309 and 0.353, and the 90% CIs for the geometric means were within 90% and 111%. The majority of the AEs were mild in severity. There were no clinically relevant changes in clinical laboratory results, physical examinations or vital sign parameters.

CONCLUSION

There were no significant differences in the steady-state pharmacokinetics of fluvastatin or amlodipine when they were administered together and the small differences observed were not clinically relevant. Therefore, no dose adjustment of either drug is necessary when fluvastatin and amlodipine are coadministered.