title: A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer.
abstract: Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.
authors.affiliation: Department of Internal Medicine, University Hospital Groningen, The Netherlands.
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: J A
authors.initials: JA
authors.lastname: Gietema
authors.forename: P
authors.initials: P
authors.lastname: Workman
authors.forename: J E
authors.initials: JE
authors.lastname: Scott
authors.forename: A
authors.initials: A
authors.lastname: Crawshaw
authors.forename: H J
authors.initials: HJ
authors.lastname: Dobbs
authors.forename: I
authors.initials: I
authors.lastname: Dennis
authors.forename: N H
authors.initials: NH
authors.lastname: Mulder
authors.forename: D T
authors.initials: DT
authors.lastname: Sleijfer
authors.forename: P H
authors.initials: PH
authors.lastname: Willemse
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D011743:Pyrimidines; C024530:piritrexim