Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: A study by the national cancer institute organ dysfunction working group

Ramesk K Ramanathan, Merrill J. Egorin, Chris H M Takimoto, Scot C. Remick, James H. Doroshow, Patricia A. LoRusso, Daniel L. Mulkerin, Jean L. Grem, Anne Hamilton, Anthony J. Murgo, Douglas M. Potter, Chandra P. Belani, Michael J. Hayes, Bin Peng, S. Percy Ivy

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Abstract

Purpose: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients and Methods: Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. Results: In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (μg/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. Conclusion: Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

Original languageEnglish (US)
Pages (from-to)563-569
Number of pages7
JournalJournal of Clinical Oncology
Volume26
Issue number4
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

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National Cancer Institute (U.S.)
Liver Diseases
Pharmacokinetics
Neoplasms
Nausea
Vomiting
Fatigue
Guidelines
Liver
Liver Function Tests
Imatinib Mesylate
Bilirubin
Area Under Curve
Edema
Urine
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction : A study by the national cancer institute organ dysfunction working group. / Ramanathan, Ramesk K; Egorin, Merrill J.; Takimoto, Chris H M; Remick, Scot C.; Doroshow, James H.; LoRusso, Patricia A.; Mulkerin, Daniel L.; Grem, Jean L.; Hamilton, Anne; Murgo, Anthony J.; Potter, Douglas M.; Belani, Chandra P.; Hayes, Michael J.; Peng, Bin; Ivy, S. Percy.

In: Journal of Clinical Oncology, Vol. 26, No. 4, 01.02.2008, p. 563-569.

Research output: Contribution to journalArticle

Ramanathan, RK, Egorin, MJ, Takimoto, CHM, Remick, SC, Doroshow, JH, LoRusso, PA, Mulkerin, DL, Grem, JL, Hamilton, A, Murgo, AJ, Potter, DM, Belani, CP, Hayes, MJ, Peng, B & Ivy, SP 2008, 'Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: A study by the national cancer institute organ dysfunction working group', Journal of Clinical Oncology, vol. 26, no. 4, pp. 563-569. https://doi.org/10.1200/JCO.2007.11.0304
Ramanathan, Ramesk K ; Egorin, Merrill J. ; Takimoto, Chris H M ; Remick, Scot C. ; Doroshow, James H. ; LoRusso, Patricia A. ; Mulkerin, Daniel L. ; Grem, Jean L. ; Hamilton, Anne ; Murgo, Anthony J. ; Potter, Douglas M. ; Belani, Chandra P. ; Hayes, Michael J. ; Peng, Bin ; Ivy, S. Percy. / Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction : A study by the national cancer institute organ dysfunction working group. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 4. pp. 563-569.
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abstract = "Purpose: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients and Methods: Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. Results: In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24{\%}), nausea/vomiting (10{\%}), fatigue (6{\%}), and edema (5{\%}). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (μg/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10{\%} of the total dose in all groups. Conclusion: Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.",
author = "Ramanathan, {Ramesk K} and Egorin, {Merrill J.} and Takimoto, {Chris H M} and Remick, {Scot C.} and Doroshow, {James H.} and LoRusso, {Patricia A.} and Mulkerin, {Daniel L.} and Grem, {Jean L.} and Anne Hamilton and Murgo, {Anthony J.} and Potter, {Douglas M.} and Belani, {Chandra P.} and Hayes, {Michael J.} and Bin Peng and Ivy, {S. Percy}",
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T1 - Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction

T2 - A study by the national cancer institute organ dysfunction working group

AU - Ramanathan, Ramesk K

AU - Egorin, Merrill J.

AU - Takimoto, Chris H M

AU - Remick, Scot C.

AU - Doroshow, James H.

AU - LoRusso, Patricia A.

AU - Mulkerin, Daniel L.

AU - Grem, Jean L.

AU - Hamilton, Anne

AU - Murgo, Anthony J.

AU - Potter, Douglas M.

AU - Belani, Chandra P.

AU - Hayes, Michael J.

AU - Peng, Bin

AU - Ivy, S. Percy

PY - 2008/2/1

Y1 - 2008/2/1

N2 - Purpose: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients and Methods: Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. Results: In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (μg/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. Conclusion: Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

AB - Purpose: To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). Patients and Methods: Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. Results: In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (± SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) were 162 ± 155, 171 ± 72, 182 ± 157, and 185 ± 172 (μg/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. Conclusion: Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.

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