PHASE-I PHARMACOKINETIC STUDY OF CYCLOSPORINE-A COMBINED WITH DOXORUBICIN

We performed a phase I trial of cyclosporin A (CsA) in combination wit h doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative to xicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infu sion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 mug/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalate d in consecutive cohorts of patients until the MTD was determined. Twe nty-three patients and 40 courses were evaluable for toxicity. Pharmac okinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 mug/kg/min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 mumo l/liter at the initiation of the infusion to a median of 40.4 mumol/li ter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung canc er and one with breast cancer, had stable disease while receiving trea tment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total b ody clearance of 0.177 liter/h/kg. The area under the concentration x time curve (AUC) increased linearly with dose of dox, and total body c learance was independent of dose. The mean total body clearance was 2. 46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at t he doses administered in this study. The ration of AUC for doxorubicin ol to AUC for dox was less than expected, suggesting that the metaboli sm and/or excretion of dox was decreased when administered with CsA. W e conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and /or excretion of dox or increased bone marrow stem cell sensitivity to dox.