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Phase I and Pharmacological Study of a New Camptothecin Derivative, Exatecan Mesylate (DX-8951f), Infused Over 30 Minutes Every Three Weeks¹

Division of Oncology/Hematology, Department of Medicine, National Cancer Center Hospital East, Kashiwa 277-8577 [H. M., H. F., T. I., K. I., Y. S.], and Daiichi Pharmaceutical Co., Ltd., Tokyo 134-8630 [K. T., T. O.], Japan

Purpose: A Phase I study of exatecan, a new water-soluble camptothecin derivative, was conducted to determine the maximum tolerated dose and a recommended dose, according to an internationally standardized core protocol. Pharmacological profiles of lactone and total (lactone + carboxylate) exatecan were also investigated.

Patients and Methods: Fifteen patients with advanced solid malignancies were treated with 3, 5, and 6.65 mg/m² of exatecan infused over 30 min every 3 weeks. Concentrations of lactone, total drug, and a metabolite in plasma and urine were determined during the first course.

Results: Dose-limiting neutropenia and liver dysfunction were observed in two of six patients at 6.65 mg/m², but no grade 3 or worse diarrhea was observed. Emesis was moderate, and no grade 3 or worse nausea and vomiting were observed at a recommended dose of 5 mg/m², with prophylactic use of granisetron. Pharmacokinetics were linear and had moderate variability; clearances of lactone and total drug were 6.8 ± 2.8 and 2.1 ± 1.1 (mean ± SD) l/h/m², respectively. The ratio of lactone concentration to total drug concentration in plasma decreased from 0.81 ± 0.06 at the end of infusion to 0.15 ± 0.06 10 h after the infusion. The lactone:total ratio of drug exposure was 0.30 ± 0.08, ranging from 0.16 to 0.43. Neutropenia was related to the drug exposure of both lactone and total drug.

Conclusions: The recommended dose of exatecan infused over 30 min every 3 weeks is 5 mg/m², with a favorable toxicity profile of mild and infrequent diarrhea. Interpatient variability of pharmacokinetics was similar to or smaller than that with other camptothecin derivatives.

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