Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD

Abstract

Aims: The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the influence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels. Methods: SDZ RAID was administered orally in different doses (0.25-15 mg day-1) to seven patients, who were on standard cyclosporin-based immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray-mass spectrometry. Results: The mean area under the blood concentration-time curve to 12 h (AUC(0,12 h)) was 4244±1311 μg l-1 h for cyclosporin before SDZ RAD treatment and 4683±1174 μg l-1 h (P=0.106) on the day of SDZ RAD treatment (95% CI for difference -126, 1003). On both study days C(max), and t(max) of cyclosporin were not significantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-normalized to 1 mg SDZ RAD were as follows: AUC(0,24 h): 35.4±13.1 μg l-1 h, C(max): 7.9±2.7 μg l-1 and t(max): 1.5±0.9 h. The metabolites of SDZ RAD found in blood were hydroxy-SDZ RAD, dihydroxy-SDZ RAD, demethyl-SDZ RAD, and a ring-opened form of SDZ RAD. Conclusions: A single dose of SDZ RAD did not influence significantly the pharmacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy-SDZ RAD, its AUC(0,24 h) being nearly half that of the parent compound SDZ RAD.