PHASE-I CLINICAL-TRIAL - PHARMACOKINETICS OF A NOVEL ANTHRACYCLINE, DA-125 AND METABOLITES - SINGLE-DOSE STUDY

Single dose of DA-125, 20 (n = 3), 40 (n = 3), 60 (n = 3), 80 (n = 6), or 100 (n = 6) mg/m(2) body surface area, was administered intravenou sly in 5 min to 21 patients with various types of cancer as phase I cl inical trial. The main side-effects of DA-125 were nausea, vomiting, l eukopenia (especially neutropenia), and thrombocytopenia. Among those, hematological side-effects increased with increased doses of DA-125. No patient developed side-effects equal to or higher than grade III up to DA-125 dose of 60 mg/m(2). However, at DA-125 dose of 80 mg/m(2), 1 out of 3 patients developed grade III leukopenia and grade IV neutro penia. Therefore, 3 additional patients participated taking the dose o f 80 mg/m(2); no patient developed side-effects equal to or higher tha n grade III. Hence, DA-125 dose increased to 100 mg/m(2). At DA-125 do se of 100 mg/m(2), 2 out of 3 patients developed side-effects equal to or higher than grade III and, therefore, 3 additional patients partic ipated taking this dose. Among the 3 additional patients, 1 patient de veloped both grade III leukopenia and neutropenia. Therefore, further accrual was stopped at this dose (100 mg/m(2)). The maximally tolerate d dose (MTD) of DA-125 was determined to be 100 mg/m(2), and the dose- limiting factor for DA-125 was bone marrow suppression. DA-125 dose of 80 mg/m(2), 80% of MTD of DA-125, was recommended as the dose for pha se II clinical trial. Cardiotoxicity was not observed in any of the 21 patients according to the ECG and RVG. Neither fever, stomatitis, dia rrhea, and renal and nervous system toxicity, nor abnormality in blood coagulation was observed in any of the patients, and death or life-th reatening side-effects due to DA-125 were also not observed. Antitumor effects of DA-125 were evaluated from the 21 patients; 6 progressive disease, 14 stable disease, and 1 partial response. Pharmacokinetic pa rameters of M1, such as AUC, t(1/2), CL, V-ss, and MRT, seemed to be i ndependent of i.v. doses of DA-125, 20 -100 mg/m(2) and less than 0.75 % of M1 were excreted in 96 h urine when expressed in terms of DA-125 iv dose. M2 was the main metabolite of DA-125 among M1-M4 excreted in urine; 10.1 similar to 22.3% of M2 was excreted in 96 h urine when exp ressed in terms of DA-125 i.v. dose. Bile was collected via the T-tube in 1 additional patient at the dose of 100 mg/m(2). Biliary excretion of M1 and M2 was negligible; less than 0.320 and 4.76% of M1 and M2, respectively, were excreted in 96 h bile when expressed in terms of DA -125 i.v, dose.