A PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF THE ORAL AND THE ORALINTRAVENOUS ADMINISTRATION OF MENOGARIL

Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at d osages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients r eceived alternating oral and IV doses of menogaril (250 mg/m2 IV; 250- 500 mg/m2 oral) with accompanying blood and urine sampling for pharmac okinetics analysis. Nausea and vomiting were the dose-limiting toxicit ies at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic ewing at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia < 3000/mul occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the pat ients receiving IV menogaril, peripheral vein phlebitis, leukopenia an d anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with non-small cell lung cancer experienced a 30% reduction in metastatic tumor nodules. For the patients receivin g alternating oral and IV menogaril, comparative pharmacokinetic analy ses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intr avenous administration. The harmonic mean (+/- SD) terminal dispositio n half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bi oavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril an d the primary metabolite, N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral m enogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chron ic low-intermediate dosages of the drug may be given orally with poten tially better tolerance and antitumor activity.