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Phase I Pharmacokinetic Study of Cyclosporin A Combined with Doxorubicin¹

Departments of Medicine [C. E., M. M.] and Biostatistics [P. G.], Princess margaret Hospital, University of Toronto, Toronto, Canada M4X 1K9; Faculty of Pharmacy, University of Toronto, Toronto, Canada M5S 2S2 [J. J. T.]; Toronto Bayview Regional Cancer Centre, University of Toronto, Canada M4N 3M5 [I. G. K., G. B.]; and Department of Pharmacy [S. W., C. D.] and Biochemistry [P. B.], Sunnybrook Health Sciences Centre, University of Toronto, Canada M4N 3M5

We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities 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 infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 µg/kg/min, and the dox starting dose was 30 mg/m². Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic 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 µg/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 µmol/liter at the initiation of the infusion to a median of 40.4 µmol/liter 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 cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body 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 clearance 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 the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We 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.

¹ This work was supported by National Cancer Institute Grant CA-52182-02.

² To whom requests for reprints should be addressed, at Princess Margaret Hospital, 500 Sherbourne Ave., Toronto, Ontario, Canada M4X 1K9.

Received 3/17/93. Accepted 8/10/93.

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