Dose-escalation study characterizes sirolimus pharmacokinetics in stable kidney transplant recipients, indicating dose-proportional exposure and racial differences in drug clearance.
Key Points
To determine the multiple-dose pharmacokinetics, dose proportionality, and potential drug interactions of sirolimus in stable renal transplant recipients receiving cyclosporine and prednisone.
Conducted a 2-week, parallel-group, ascending-dose clinical study in 40 stable renal transplant patients receiving concomitant cyclosporine and prednisone.
Evaluated nine oral sirolimus dose levels ranging from 0.5 to 6.5 mg/m²/12 hr to calculate steady-state pharmacokinetic parameters and assess cyclosporine interactions.
Sirolimus exhibited a mean time to peak blood concentration of 1.4 ± 1.2 hours, a terminal half-life of 62 ± 16 hours, and an oral dose clearance of 208 ± 95 mL/h/kg, with 4.5-fold intersubject variability.
Steady-state trough blood concentrations correlated strongly with area under the concentration-time curve (AUC), while sirolimus co-administration caused no significant change in cyclosporine AUC.
Preliminary assessments demonstrated linear dose proportionality and identified pharmacokinetic differences between Black and non-Black patients, with no significant differences observed between genders.