title: Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer.
abstract: OBJECTIVE
  This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability.
  
  
  METHODS
  Patients received a 10-min infusion of 600 to 14,00 mg/m(2) pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1.
  
  
  RESULTS
  Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m(2) were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation.
  
  
  CONCLUSIONS
  The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m(2) in LPT patients and 800 mg/m(2) in HPT patients, irrespective of the type of vitamin supplementation.
authors.affiliation: Institute for Drug Development at the Cancer Therapy and Research Center and University of Texas Health Science Center, San Antonio, Texas 78245-3217, USA. ctakimot@idd.org
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond-Thelin
authors.forename: Jane E
authors.initials: JE
authors.lastname: Latz
authors.forename: Leonardo
authors.initials: L
authors.lastname: Forero
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Bahram
authors.initials: B
authors.lastname: Forouzesh
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Pamela
authors.initials: P
authors.lastname: Monroe
authors.forename: Leslie
authors.initials: L
authors.lastname: Wood
authors.forename: Karen B
authors.initials: KB
authors.lastname: Schneck
authors.forename: Romnee
authors.initials: R
authors.lastname: Clark
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000627:therapeutic use; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D000068437:Pemetrexed; D014803:Vitamin B Complex / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D014803:Vitamin B Complex; D006147:Guanine; D005492:Folic Acid