title: Pharmacokinetics of Brequinar sodium (NSC 368390) in patients with solid tumors during a phase I study.
abstract: The pharmacokinetics of the novel antipyrimidine agent Brequinar sodium (NSC 368390; DUP 785) was studied in 23 patients with solid tumors during the phase I study of this compound. The drug was administered by short-term (10-60 min) intravenous infusion every 3 weeks. The doses ranged from 15 to 2250 mg/m2. At doses higher than 1500 mg/m2 the areas under the plasma concentration vs. time curve (AUC) increased non-proportionally, while the total body clearance (Clt) dropped substantially, indicating non-linear pharmacokinetics of the drug. Brequinar sodium showed a triphasic decay of plasma concentrations with half-life ranges of 11.1-36.6 min, 1.7-6.9 h and 12.5-25.0 h, respectively. The volume of distribution (Vdss) ranged from 4.4 to 10.6 l/m2. The total body clearance (Clt) ranged from 6.9 to 22.1 ml/min with a small contribution of the renal clearance (0.04-0.4 ml/min). Up to 7 days, the cumulative urinary excretion (CUE) and the cumulative fecal excretion (CFE) ranged from 0.4 to 8.3% and from 7.7 to 18.3% of the dose, respectively. There was evidence for the presence of drug metabolites in urine and feces. There was no drug accumulation with repeated administration of Brequinar sodium by the above mentioned drug schedule. The ratio between the plasma AUC at the maximum tolerable dose (MTD) in man and that at the mouse LD10 was 0.8, while the ratio between the respective doses was 5.7. The ratios between the AUC in patients and that at the mouse LD10 were applied to guide dose escalation in the phase I study. The results of the above mentioned pharmacokinetic studies were useful for the choice of an optimal schedule for phase II trials of Brequinar sodium.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Schwartsmann
authors.forename: W J
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: M B
authors.initials: MB
authors.lastname: van Hennik
authors.forename: I
authors.initials: I
authors.lastname: Klein
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: P
authors.initials: P
authors.lastname: Dodion
authors.forename: W W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: G
authors.initials: G
authors.lastname: Joggi
authors.forename: H
authors.initials: H
authors.lastname: Gall
authors.forename: N
authors.initials: N
authors.lastname: Crespeigne
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011798:Quinaldines
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C046943:brequinar; D011798:Quinaldines