title: Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function.
abstract: OBJECTIVE
  This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.
  
  
  METHODS
  Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12.
  
  
  RESULTS
  Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2.
  
  
  CONCLUSIONS
  Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, 78229, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Andrew
authors.initials: A
authors.lastname: Goetz
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Miguel
authors.initials: M
authors.lastname: Villalona-Calero
authors.forename: Alan
authors.initials: A
authors.lastname: Sandler
authors.forename: Tuhin
authors.initials: T
authors.lastname: Chaudhuri
authors.forename: Kathleen
authors.initials: K
authors.lastname: Molpus
authors.forename: Jane E
authors.initials: JE
authors.lastname: Latz
authors.forename: Lorinda
authors.initials: L
authors.lastname: Simms
authors.forename: Ajai K
authors.initials: AK
authors.lastname: Chaudhary
authors.forename: Robert D
authors.initials: RD
authors.lastname: Johnson
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D013921:Thrombocytopenia / Q000139:chemically induced; D014805:Vitamin B 12 / Q000008:administration & dosage
chemical_list: D000964:Antimetabolites, Antineoplastic; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12