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In this 2-week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5-6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 +/- 1.2 hours; terminal half-life, 62 +/- 16 hours; oral dose clearance, 208 +/- 95 mL/h/kg; apparent oral steady-state volume of distribution, 12 +/- 5 L/kg; and blood/plasma ratio, 38 +/- 13. The intersubject variabilities in dose clearance, steady-state volume of distribution, and blood/plasma ratio were 4.5-fold. Preliminary assessments suggests linear dose proportionality. An excellent correlation existed between area under the concentration-time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration-time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.

This report provides an initial population pharmacokinetics of sirolimus in kidney transplant recipients receiving cyclosporine concurrently. Sirolimus blood and plasma pharmacokinetics were biexponential and linear for doses from 3 to 15 mg/m2. No pharmacokinetic interaction was found between sirolimus and cyclosporine.

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