Phase I and pharmacological study of a new camptothecin derivative, exatecan mesylate (DX-8951f), infused over 30 minutes every three weeks.

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/m(2) 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/m(2), 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/m(2), 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/m(2), 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/m(2), 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.