Pharmacokinetic interaction between single oral doses of ditiazem and sirolimus in healthy volunteers

Aim and Background: The pharmacokinetic interaction between sirolimus, a ma crolide immunosuppressant metabolized by CYP3A4, and the calcium channel bl ocker diltiazem was studied in 18 healthy subjects, Several clinically impo rtant interactions have previously been reported for other immunosuppressiv e drugs that are metabolized by the same enzyme and for calcium antagonists . Methods: Healthy subjects who were 20 to 43 years old participated in an op en, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem , and the two drugs given together. The three study periods were separated by a 21-day washout phase. Results: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), fr om 736 to 1178 ng.h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elim ination half-life of sirolimus decreased slightly, from 79 to 67 hours, App arent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The pl asma maximum concentration and area under the plasma concentration-time cur ve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiogr aphic parameters was seen. Conclusions: Single-dose diltiazem coadministration leads to higher sirolim us exposure, presumably by inhibition of the first-pass metabolism of sirol imus, Because of the pronounced intersubject variability in the extent of t he sirolimus-diltiazem interaction, whole blood sirolimus concentrations sh ould be monitored closely in patients treated with the two drugs.