Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and leukemia group B 9565

Alan P. Venook, Merrill J. Egorin, Gary L. Rosner, Donna Hollis, Sridhar Mani, Michael Hawkins, John Byrd, Raymond Hohl, Daniel Budman, Neal J. Meropol, Mark J. Ratain

Research output: Contribution to journalArticle

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Abstract

Purpose: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. Patients and Methods: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dl.; II-bilirubin level 1.6 to 7.0 mg/dl.; and III-creatinine level 1.6 to 5.0 mg/dl. with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. Results: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups of compared with historical controls. Conclusions: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation. (C) 2000 by American Society of Clinical Oncology.

Original languageEnglish (US)
Pages (from-to)2780-2787
Number of pages8
JournalJournal of Clinical Oncology
Volume18
Issue number14
DOIs
StatePublished - Jan 1 2000

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gemcitabine
Kidney Neoplasms
Leukemia
Pharmacokinetics
Liver
Bilirubin
Creatinine

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Venook, Alan P. ; Egorin, Merrill J. ; Rosner, Gary L. ; Hollis, Donna ; Mani, Sridhar ; Hawkins, Michael ; Byrd, John ; Hohl, Raymond ; Budman, Daniel ; Meropol, Neal J. ; Ratain, Mark J. / Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction : Cancer and leukemia group B 9565. In: Journal of Clinical Oncology. 2000 ; Vol. 18, No. 14. pp. 2780-2787.
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title = "Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and leukemia group B 9565",
abstract = "Purpose: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. Patients and Methods: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dl.; II-bilirubin level 1.6 to 7.0 mg/dl.; and III-creatinine level 1.6 to 5.0 mg/dl. with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. Results: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups of compared with historical controls. Conclusions: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation. (C) 2000 by American Society of Clinical Oncology.",
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Venook, AP, Egorin, MJ, Rosner, GL, Hollis, D, Mani, S, Hawkins, M, Byrd, J, Hohl, R, Budman, D, Meropol, NJ & Ratain, MJ 2000, 'Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and leukemia group B 9565', Journal of Clinical Oncology, vol. 18, no. 14, pp. 2780-2787. https://doi.org/10.1200/JCO.2000.18.14.2780

Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction : Cancer and leukemia group B 9565. / Venook, Alan P.; Egorin, Merrill J.; Rosner, Gary L.; Hollis, Donna; Mani, Sridhar; Hawkins, Michael; Byrd, John; Hohl, Raymond; Budman, Daniel; Meropol, Neal J.; Ratain, Mark J.

In: Journal of Clinical Oncology, Vol. 18, No. 14, 01.01.2000, p. 2780-2787.

Research output: Contribution to journalArticle

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T1 - Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction

T2 - Cancer and leukemia group B 9565

AU - Venook, Alan P.

AU - Egorin, Merrill J.

AU - Rosner, Gary L.

AU - Hollis, Donna

AU - Mani, Sridhar

AU - Hawkins, Michael

AU - Byrd, John

AU - Hohl, Raymond

AU - Budman, Daniel

AU - Meropol, Neal J.

AU - Ratain, Mark J.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - Purpose: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. Patients and Methods: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dl.; II-bilirubin level 1.6 to 7.0 mg/dl.; and III-creatinine level 1.6 to 5.0 mg/dl. with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. Results: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups of compared with historical controls. Conclusions: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation. (C) 2000 by American Society of Clinical Oncology.

AB - Purpose: To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. Patients and Methods: Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dl.; II-bilirubin level 1.6 to 7.0 mg/dl.; and III-creatinine level 1.6 to 5.0 mg/dl. with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. Results: Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups of compared with historical controls. Conclusions: If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation. (C) 2000 by American Society of Clinical Oncology.

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