Phase I clinical and pharmacokinetic trial of oral menogaril administered on three consecutive days

• Published in: European journal of cancer & clinical oncology Vol. 24; no. 6; pp. 1019 - 1026
• Main Authors: Dodion, P., De Valeriola, D., Crespeigne, N., Peeters, B., Wery, F., Van Berchem, C., Piccart, M., Tueni, E., Joggi, J., Kenis, Y.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.1988; New York, NY Pergamon Press
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biological Availability; Chemotherapy; Daunorubicin - analogs & derivatives; Drug Evaluation; Female; Half-Life; Humans; Leukopenia - chemically induced; Male; Medical sciences; Menogaril; Middle Aged; Neoplasms - blood; Nogalamycin - administration & dosage; Nogalamycin - adverse effects; Nogalamycin - analogs & derivatives; Nogalamycin - blood; Pharmacology. Drug treatments; Antineoplastic agent; Human; Solid tumor; Chemotherapy; Leukopenia; Toxicity; Oral administration; Phase I trial; Adult; Pharmacokinetics
• ISSN: 0277-5379
• DOI: 10.1016/0277-5379(88)90152-6

Eighteen adult patients with solid tumors were treated with oral menogaril, a new anthracycline antibiotic active against human breast cancer after intravenous administration. The drug was given orally on 3 consecutive days every 4 weeks at doses ranging from 50 to 175 mg/m 2 /day. Reversible and dose-related leukopenia was the dose-limiting toxicity. Thrombocytopenia was less frequent. Hematologic toxicity was maximal usually 2 weeks after treatment and recovery usually occurred within 4 weeks. At doses from 50 to 150 mg/m 2 /day, non-hematologic side-effects patient), alopecia (two patients), mucositis (two patients) and liver function test abnormalities (three patients). The single patient treated at a daily dose of 175 mg/m 2 /day developed grade IV leucothrombocytopenia, with fever and gastrointestinal bleeding. This was followed by heart failure and the patient died from multisystem organ failure. Peak plasma concentrations of menogaril ranged from 0.043 to 0.409 μM and were linearly correlated with the dose. Similarly, the area under the plasma concentration versus time curve varied from 0.33 to 9.59 μM × h and was linearly correlated with the dose. The mean harmonic half-life was 11.3 ± 6.4 h. A comparison of the data from the present trial and our previous study with intravenous menogaril indicates a bioavailability of 32 ± 12%. There was an excellent relationship between the white blood cell decrease (as a percentage of the pretreatment value) and several pharmacokinetic parameters; the best correlation was obtained with the plasma concentration of menogaril at 4 h after treatment. A dose of 150 mg/m 2 /day for 3 consecutive days is recommended for phase II trials with oral menogaril but the bioavailability of the drug should be monitored carefully and, more specifically, the concept of a pharmacokinetic adjustment of the dose of menogaril should be evaluated prospectively.