Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function

Alain C. Mita, Christopher J. Sweeney, Sharyn D. Baker, Andrew Goetz, Lisa A. Hammond, Amita Patnaik, Anthony W. Tolcher, Miguel Villalona-Calero, Alan Sandler, Tuhin K Chaudhuri, Kathleen Molpus, Jane E. Latz, Lorinda Simms, Ajai K. Chaudhary, Robert D. Johnson, Eric K. Rowinsky, Chris H. Takimoto

Research output: Contribution to journalArticle

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Abstract

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 (r 2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m 2 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.

Original languageEnglish (US)
Pages (from-to)552-562
Number of pages11
JournalJournal of Clinical Oncology
Volume24
Issue number4
DOIs
StatePublished - Feb 1 2006
Externally publishedYes

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Pemetrexed
Pharmacokinetics
Kidney
Neoplasms
Glomerular Filtration Rate
Vitamins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Mita, Alain C.; Sweeney, Christopher J.; Baker, Sharyn D.; Goetz, Andrew; Hammond, Lisa A.; Patnaik, Amita; Tolcher, Anthony W.; Villalona-Calero, Miguel; Sandler, Alan; Chaudhuri, Tuhin K; Molpus, Kathleen; Latz, Jane E.; Simms, Lorinda; Chaudhary, Ajai K.; Johnson, Robert D.; Rowinsky, Eric K.; Takimoto, Chris H.

In: Journal of Clinical Oncology, Vol. 24, No. 4, 01.02.2006, p. 552-562.

Research output: Contribution to journalArticle

Mita, AC, Sweeney, CJ, Baker, SD, Goetz, A, Hammond, LA, Patnaik, A, Tolcher, AW, Villalona-Calero, M, Sandler, A, Chaudhuri, TK, Molpus, K, Latz, JE, Simms, L, Chaudhary, AK, Johnson, RD, Rowinsky, EK & Takimoto, CH 2006, 'Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function', Journal of Clinical Oncology, vol. 24, no. 4, pp. 552-562. https://doi.org/10.1200/JCO.2004.00.9720
Mita, Alain C. ; Sweeney, Christopher J. ; Baker, Sharyn D. ; Goetz, Andrew ; Hammond, Lisa A. ; Patnaik, Amita ; Tolcher, Anthony W. ; Villalona-Calero, Miguel ; Sandler, Alan ; Chaudhuri, Tuhin K ; Molpus, Kathleen ; Latz, Jane E. ; Simms, Lorinda ; Chaudhary, Ajai K. ; Johnson, Robert D. ; Rowinsky, Eric K. ; Takimoto, Chris H. / Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 4. pp. 552-562.
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abstract = "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 (r 2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m 2 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.",
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T1 - Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function

AU - Mita, Alain C.

AU - Sweeney, Christopher J.

AU - Baker, Sharyn D.

AU - Goetz, Andrew

AU - Hammond, Lisa A.

AU - Patnaik, Amita

AU - Tolcher, Anthony W.

AU - Villalona-Calero, Miguel

AU - Sandler, Alan

AU - Chaudhuri, Tuhin K

AU - Molpus, Kathleen

AU - Latz, Jane E.

AU - Simms, Lorinda

AU - Chaudhary, Ajai K.

AU - Johnson, Robert D.

AU - Rowinsky, Eric K.

AU - Takimoto, Chris H.

PY - 2006/2/1

Y1 - 2006/2/1

N2 - 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 (r 2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m 2 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.

AB - 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 (r 2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m 2 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.

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