Assessment of pharmacokinetic interactions between ezetimibe and cyclosporine

Abstract

Aims Dyslipidemia is often under-treated in patients on cyclosporine (CyA) due to potentially clinically significant statin drug interactions. Thus, the pharmacokinetic (PK) interactions between the intestinal cholesterol absorption inhibitor ezetimibe (EZE) and CyA were explored. Methods Study 1: 1 period in 8 renal transplant (txp) patients with normal renal function to assess single-dose (SD) total EZE (EZE+ EZE-glucuronide) AUC0-last (120h sampling) and Cmax of EZE 10 mg during steady-state CyA (75–150 mg b.i.d.). Study 2: 2-period crossover in 12 healthy subjects to assess SD AUC0-last (48h sampling) and Cmax of CyA alone (100 mg) and after multiple doses (MD) of EZE 20 mg/d x7d. Results Study 1: Total EZE AUC0-last and Cmax were 3.4- and 3.9-fold higher (p≤0.001), respectively, in txp patients on CyA versus historical healthy controls (N=17) but did not exceed the highest AUC observed in patients given 50 mg/d in prior EZE MD PK studies. Study 2: MD EZE 20 mg increased CyA AUC0-last by 15%; 90% CI (7%, 25%) was within prespecified similarity bounds. No significant difference in CyA Cmax was observed (p>0.050). EZE and CyA were well-tolerated in both studies. Conclusions The clinical significance of these findings is unknown. Although the mean EZE AUC with CyA is within bounds of exposures in prior MD PK studies, the long-term clinical safety implications have not been determined. EZE+ CyA should be managed with appropriate caution and monitoring of CyA levels. Clinical Pharmacology & Therapeutics (2005) 77, P75–P75; doi: 10.1016/j.clpt.2004.12.179