Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency

We report a patient with renal insufficiency (creatinine clearance, CL(cr) = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m(2) day(-1)), thiotepa (120 mg/m(2) day(-1)) and carboplatin (AUC = 5 mg min/mL day(-1)) for four consecutive days.

Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined.

Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%.

These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insufficiency.