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Medline ® Abstract for Reference 50

of 'Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia'

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 RK, Egorin MJ, Takimoto CH, Remick SC, Doroshow JH, LoRusso PA, Mulkerin DL, Grem JL, Hamilton A, Murgo AJ, Potter DM, Belani CP, Hayes MJ, Peng B, Ivy SP, National Cancer Institute Organ Dysfunction Working Group
J Clin Oncol. 2008;26(4):563.
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 (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/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.
Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259, USA. rramanathan@tgen.org