Pharmacokinetic interactions between microemulsion formulated cyclosporineA and diltiazem in renal transplant recipients

Objective: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic inte ractions have previously been investigated, however, not with the new micro emulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of d iltiazem have not previously been investigated. We performed a pharmacokine tic interaction study in renal transplant recipients, measuring both unmeta bolised CsA and diltiazem in addition to three of the main metabolites of d iltiazem (M-A, M-1, M-2). Methods: Nine CsA-treated renal transplant patients were treated with dilti azem, 90-120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were pe rformed both before and at the end of the diltiazem treatment period. Six n on-CsA-treated renal transplant patients served as controls of CsA interact ions with diltiazem and its metabolites. Results: Diltiazem treatment resulted in a significant mean increase in the area under the concentration-time curve (AUC) for CsA of 51(8)% (P < 0.008 ) and a peak concentration (C-max) of 34(8)% (P < 0.05), without altering t ime to peak concentration (t(max)). CsA, however, did not significantly inf luence diltiazem pharmacokinetics, though two of the metabolites (M-1 and M -2) tended to be increased. Conclusions: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, ho wever, did not show significant interaction with diltiazem pharmacokinetics .