title: Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule.
abstract: Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: J
authors.initials: J
authors.lastname: Miser
authors.forename: R J
authors.initials: RJ
authors.lastname: Wells
authors.forename: W A
authors.initials: WA
authors.lastname: Bleyer
authors.forename: T E
authors.initials: TE
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Gillespie
authors.forename: J S
authors.initials: JS
authors.lastname: Penta
authors.forename: N J
authors.initials: NJ
authors.lastname: Clendeninn
authors.forename: D G
authors.initials: DG
authors.lastname: Poplack
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002648:Child; D004341:Drug Evaluation; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; C024530:piritrexim