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Pharmacokinetic and Phase I Evaluation of Esorubicin (4'-Deoxydoxorubicin) by Continuous Infusion over Forty-eight Hours in Patients with Leukemia¹

Division of Hematology/Oncology, Department of Medicine, North Shore University Hospital and Cornell Medical College, Manhasset, New York 11030 [W. K., C. R., D. R. B., P. S., S. L. A., L. W., V. V.], and Ciba-Geigy Corporation, Ardsley, New York 10505 [K. C.]

Sixteen patients with previously treated acute nonlymphocytic leukemia or chronic myelogenous leukemia in blast crisis were given one to three courses of esorubicin by continuous infusion over 48 h. Dosage levels extended from 35 to 85 mg/m². Four patients showed partial responses of short duration. Nonhematological toxicity observed at dosages of 55 to 85 mg/m² were mucositis, diarrhea, skin rash, transaminitis, nausea, vomiting, and cardiac dysfunction. One patient receiving 85 mg/m² developed acute floid congestive heart failure within hours of administration of the drug. Pharmacokinetic analysis revealed large interpatient variation in plasma drug levels. At the end of infusion, plasma decay of esorubicin was rapid initially but slow thereafter, with a terminal half-life of 20 to 54 h. The metabolite 4'-deoxy-13-hydroxydoxorubicin reached significant plasma levels. Total body clearance, renal clearance, volume of distribution at steady state, and mean residence time show little variation during dose escalation for both esorubicin and 4'-deoxy-13-hydroxydoxorubicin. Urinary excretion of esorubicin and 4'-deoxy-13-hydroxydoxorubicin accounted for 10.5 and 1.5%, respectively, of the administered dose.

¹ This work was supported in part by grants from the Don Monti Memorial Research Foundation and Adria Laboratories, Dublin, OH.

² To whom requests for reprints should be addressed.

Received 2/24/88. Revised 6/23/88. Accepted 7/ 5/88.