Correlation Between Pretransplantation Test Dose Cyclosporine Pharmacokinetic Profiles and Posttransplantation Sirolimus Blood Levels in Renal Transplant Recipients

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Abstract
We sought to determine whether pretransplantation test dose pharmacokinetic measurements of cyclosporine (CsA) concentrations would forecast the posttransplantation blood concentrations of sirolimus in renal transplant patients treated de novo with CsA, sirolimus, and prednisone. All 44 renal transplant recipients enrolled in Phase I/II studies of de novo posttransplantation therapy with sirolimus, CsA, and prednisone underwent pretransplantation pharmacokinetic profiling after having received paired intravenous (IV) and oral test doses of CsA. After transplantation, all patients were treated with CsA on a once- or twice-daily schedule (according to a concentration-controlled regimen), with tapering doses of prednisone, and with fixed doses of sirolimus on a once-daily schedule. Patients were divided into four cohorts based on the deviation of their pretransplantation CsA clearance or bioavailability values from the mean. Patients with high pretransplantation CsA clearance rates displayed a significantly lower mean posttransplantation value of sirolimus trough concentrations than patients with low pretransplantation CsA clearance rates. In contrast, values for pretransplantation absolute oral CsA bioavailability failed to correlate with the mean posttransplantation concentration of sirolimus but did predict posttransplantation CsA bioavailability. Therefore, pretransplantation CsA clearance rate estimates may forecast posttransplantation sirolimus concentrations, possibly guiding use of sirolimus therapy to achieve an optimal ratio of concentration-dependent immunosuppressive versus toxic effects.