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Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) administered with an oral folic acid supplement

Lookup NU author(s): Professor Steve Wedge, Gordon Taylor, Professor Alan Boddy, Professor Alan Calvert, Professor Herbie Newell


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(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) is an antipurine antifolate which selectively inhibits glycinamide ribonucleotide formyltransferase. Lometrexol pharmacokinetics were evaluated in 17 patients (32 courses) as part of a Phase I study in which folic acid supplementation was used to improve tolerance to the drug, its clinical utility being previously limited by severe cumulative toxicity, Lometrexol was administered as an i.v. bolus every 4 weeks at a starting dose of 12 mg/m(2), with subsequent interpatient dose escalation to 16, 30, and 45 mg/m(2), p.o. folic acid (5 mg/day) was given for 7 days before and 7 days after lometrexol administration, The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater), Mean plasma half-lives (+/- SD) for model-dependent analysis were t(1/2)alpha 19 +/- 7 min, t(1/2)beta 256 +/- 96 min, and t(1/2)gamma (where measurable) 1170 +/- 435 min, Lometrexol area under plasma concentration versus time curve was proportional to the dose administered, Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin, The volume of distribution of lometrexol at steady state was between 4.7 and 15.8 l/m(2), Renal elimination of lometrexol, studied in 19 patients (21 courses), was considerable, accounting for 56 +/- 17% of the total dose administered within 6 h of treatment, and 85 +/- 16% within 24 h of treatment, These recoveries of unchanged lometrexol indicate that the drug does not appear 60 undergo appreciable systemic metabolism at the range of concentrations studied.

Publication metadata

Author(s): Wedge SR, Laohavinij S, Taylor GA, Boddy AV, Calvert AH, Newell DR

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 1995

Volume: 1

Issue: 12

Pages: 1479-1486

Print publication date: 01/12/1995

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265


PubMed id: 9815947