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

Abstract

Purpose We report a patient with renal insuYciency (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. Methods 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. Results 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%. Conclusion 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 insuYciency.

Double‐conditioning regimen consisting of high‐dose thiotepa and melphalan with autologous stem cell rescue for high‐risk pediatric solid tumors: A second report

“…However, the latter report also showed that renal insufficiency was associated with longer duration of fever and hospitalization, and seemed to be related to the adverse effects of melphalan . In a case report on the pharmacokinetics of thiotepa in a patient with renal insufficiency, the patient experienced excessive exposure to tepa, an active metabolite of thiotepa . Taken together, these findings suggest that it is reasonable to reduce doses of thiotepa and melphalan according to the patient's Ccr.…”

Cyclophosphamide in dermatology

“…2 There is a small amount of data which shows that renal impairment increases systemic drug exposure, but data does not demonstrate clinically relevant changes. 2,23,24 Before the drug is administered the severity of renal impairment should be considered. 2 Table 2 lists some drug-drug interactions with cyclophosphamide.…”

Reduced Methotrexate Clearance and Renal Impairment in a Boy With Osteosarcoma and Earlier Undetected Autosomal Dominant Polycystic Kidney Disease (ADPKD)

“…When renal function is compromised, drug and metabolites eliminated through the kidneys may accumulate to toxic levels with repeated dosing. 14 We report here on a 12-year-old boy with osteosarcoma undergoing chemotherapy with doxorubicin, cisplatin, methotrexate, ifosfamide, and etoposide. Renal elimination of doxorubicin accounts for only 5% to 15% and is therefore less important concerning renal impairment.…”