Originally published as JCO Early Release 10.1200/JCO.2004.00.9720 on January 3 2006

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Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal Function

From the Institute for Drug Development at the Cancer Therapy and Research Center; Nuclear Medicine Department, The University of Texas Health Science Center, San Antonio, TX; Indiana University Cancer Center; and Eli Lilly and Company, Indianapolis, IN.

Address reprint requests to Chris H. Takimoto, MD, PhD, Institute for Drug Development, Cancer Therapy and Research Center; 7979 Wurzbach Rd, 4th Floor Zeller Building, San Antonio, TX, 78229; e-mail: ctakimot{at}idd.org

PURPOSE: 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.

PATIENTS AND 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 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 nonsupplemented 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 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m².

CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m² with vitamin supplementation in patients with GFR 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.

Supported by Eli Lilly and Company.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001, and the 27th European Society for Medical Oncology Congress, Nice, France, October 18-22, 2002.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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