Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients

Objective: The mutual drug-drug interaction potential of the 3-hydroxy-3-me thylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cycl osporine (INN, ciclosporin) in kidney transplant recipients receiving indiv idual immunosuppressive treatment was evaluated with respect to pharmacokin etic behavior of either drug and tolerability of concomitant use. Methods: Plasma and urine concentrations of cerivastatin and its major meta bolites were determined after administration of 0.2 mg single-dose cerivast atin to 12 kidney transplant recipients (9 men and 3 women) who were receiv ing stable individual cyclosporine treatment (mainly 200 mg twice a day). T hese results were compared with the single-dose pharmacokinetic results obt ained from a healthy control group (n = 12, age-comparable men). Cerivastat in steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day tr eatment of 0.2 mg cerivastatin once a day, Cyclosporine steady-state concen tration-time profiles were determined in blood with monoclonal (EMIT [enzym e multiplied immunoassay technique] assay, parent drug specific) and polycl onal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclos porine plus metabolites) during cerivastatin cotreatment and compared with predosing data. Results: Coadministration of 0.2 mg cerivastatin once a day to the kidney t ransplant recipients treated with individual doses of cyclosporine and othe r immunosuppressive agents resulted in a 3- to 5-fold increase in cerivasta tin and metabolites plasma concentrations. Cerivastatin and metabolites eli mination half-lives were unaffected, and no accumulation occurred during mu ltiple-dosing conditions. Cerivastatin had no influence on steady-state blo od concentrations of cyclosporine or cyclosporine metabolites in these pati ents. The concomitant use of both drugs was well tolerated. Conclusions: Cerivastatin and metabolites plasma concentrations were signif icantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for ce rivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes reap explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.