Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens

Purpose: Cyclophosphamide and thioTEPA are frequently used simultaneously i ll high-dose chemotherapy regimens. During a pharmacokinetic study of 31 co urses in 20 patients of cyclophosphamide and its activated metabolite 4-hyd roxycyclophosphamide given in the combination cyclophosphamide-thioTEPA-car boplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was o bserved immediately after the start of the thioTEPA infusion. A drug-drug i nteraction was suspected. This putative interaction was investigated in thi s study. Methods: Possible sequence dependency, due to inhibition of the fo rmation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by alter ing the sequence of infusion in three patients (four courses) receiving hig h-dose chemotherapy with cyclophosphamide (1000 or 1500 mg/m(2) per day), t hioTEPA (80 or 120 mg/m(2) per day) and carboplatin (265 or 400 mg/m(2) pet day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investiga ted in human microsomes. Results: A striking sequence dependency of the pha rmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased C-max (-62%) a nd AUC (-26%) values of 4-hydroxycyclophosphamide compared to those of thio TEPA administered I h after cyclophosphamide. In human microsomes an inhibi tion of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC50 of 23 mu M. No inhibition of the formation of TEPA by cyclophosphamide was ob served. Conclusions: Thio-TEPA strongly inhibits the bioactivation of cyclo phosphamide and this may decrease both efficacy and toxicity. Our results s eriously question the practice of the simultaneous continuous infusion of c yclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance.