Background: Intravenous temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved for the treatment of advanced renal cell carcinoma (RCC). Sirolimus, the principal metabolite of temsirolimus in humans, also exhibits mTOR inhibitory activity.
Objective: The purpose of this study was to compare the pharmacokinetics of temsirolimus and its metabolite, sirolimus, among patients with RCC not receiving dialysis and those receiving hemodialysis.
Methods: This was a single-center, unblinded, single-dose study. Patients with histologically confirmed metastatic RCC were eligible. A single 25-mg dose of temsirolimus was administered as a 30-minute intravenous infusion during the first round of chemotherapy. Blood samples were drawn at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5, 24, 72, and 144 hours after infusion. In patients receiving hemodialysis, an additional blood sample was drawn 1 hour after each treatment to compare pre- and postconcentration. Temsirolimus concentrations were assayed in blood using HPLC coupled to mass spectrometry. Pharmacokinetic parameters (C(max), T(max), t((1/2)), AUC(0-infinity), total body clearance, volume of distribution at steady state, AUC ratio [the ratio of sirolimus to temsirolimus AUCs], and AUC sum [the algebraic sum of temsirolimus and sirolimus AUCs]) were calculated and analyzed statistically.
Results: In total, 13 consecutive patients (11 men and 2 women; 11 not receiving dialysis and 2 receiving hemodialysis) were included. No patient refused to participate in the study. Of those not receiving dialysis, the median age was 54 years (range, 36-77 years), and of those receiving hemodialysis, the median age was 60.5 years (60-61 years). There were no significant between-group differences in the pharmacokinetic parameters of temsirolimus and sirolimus. Moreover, in patients receiving hemodialysis, blood drug concentrations assessed immediately before hemodialysis were similar to those assayed 1 hour after the treatment.
Conclusion: This study found that after single-dose administration of 25 mg of temsirolimus as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected in these patients with RCC receiving hemodi-alysis compared with those not receiving dialysis.