title: A phase I clinical and pharmacokinetic study of the oral and the oral/intravenous administration of menogaril.
abstract: Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250-500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics 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/microliters occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and 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 receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses 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 intravenous administration. The harmonic mean (+/- SD) terminal disposition half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bioavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral menogaril 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 chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: T D
authors.initials: TD
authors.lastname: Brown
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: R H
authors.initials: RH
authors.lastname: Earhart
authors.forename: W J
authors.initials: WJ
authors.lastname: Adams
authors.forename: J E
authors.initials: JE
authors.lastname: Brewer
authors.forename: J D
authors.initials: JD
authors.lastname: Hosley
authors.forename: D A
authors.initials: DA
authors.lastname: Kasunic
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D017290:Menogaril / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged
chemical_list: D015507:Drugs, Investigational; D017290:Menogaril