Pharmacokinetics of cyclosporine in heart transplant recipients receiving metabolic inhibitors

Background: Inhibitors of cyclosporine metabolism are commonly co-administe red with cyclosporine in transplant recipients. The aim of this study was t o compare cyclosporine pharmacokinetics using the conventional formulation (Sandimmune) and after switching to the microemulsion (Neoral) formulation, in stable heart transplant recipients receiving various cyclosporine metab olic inhibitors. Methods: Steady-state blood concentration-time profiles of Sandimmune were studied in 47 transplant recipients receiving either cyclosporine alone (Gr oup A, n = 11) or in combination with diltiazem (120 mg/day, Group B, n = 1 1), ketoconazole (200 mg/day, Group C, n = 13), or both ketoconazole and di ltiazem (200 and 120 mg/day, respectively, Group D, n = 12), and restudied 1 week after switching to Neoral. Results: Neoral resulted in more rapid cyclosporine absorption as judged by the shorter absorption half-lives in all groups (p < 0.05). The mean perce ntage increase in the values of area-under-the-concentration-time curve was 42% and 37.5% higher for Neoral compared with Sandimmune for Groups A and B, respectively, but only 5.4% higher for Group C and 9.5% higher for Group D. The mean morning trough concentration of cyclosporine was not significa ntly different after administration of Neoral compared with Sandimmune in a ny of the groups studied (179 vs 167 <mu>g/liter for Group A; 171 vs 147 mu g/liter for Group B; 189 vs 194 mug/liter for Group C; and 181 vs 201 mug/l iter for Group D). Neoral did not alter serum concentrations of sodium, pot assium, creatinine, and urea in any of the study groups. Conclusions: The faster absorption and improved bioavailability of cyclospo rine (around 40%) with Neoral compared with Sandimmune was not seen in pati ents receiving ketoconazole, where in fact cyclosporine bioavailability was already maximal. Mean morning trough levels of cyclosporine did not reflec t the improvement in bioavailability seen in patients switching from Sandim mune to Neoral. Cyclosporine dose adjustment may be needed when switching f rom Sandimmune to Neoral for patients not receiving sparing agents or who r eceive diltiazem, but trough levels cannot necessarily be relied upon to de termine the degree of adjustment needed. For patients on ketoconazole, the absorption profile is already optimized and no dosage alteration seems nece ssary.