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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 563-569 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.0304 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
From the Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine; the Biostatistics Department, University of Pittsburgh Graduate School of Public Health; and the Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA; the University of Texas, San Antonio, TX; Case Western Reserve University, Cleveland, OH; City of Hope National Medical Center, Duarte, CA; Wayne State University, Detroit, MI; the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI; New York University, New York, NY; the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute; the National Naval Medical Center, Bethesda, MD; and Novartis Pharmaceuticals, East Hanover, NJ Corresponding author: Ramesh K. Ramanathan, MD, Translational Genomics Research Institute, 13208 E Shea Blvd, Ste 100, Scottsdale, AZ 85259; e-mail: rramanathan{at}tgen.org 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- 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. Supported in part by Grant Nos. UO1-CA69855, P30CA47904, and NIH/NCCR/GCRC #5M01 RR 00056 from the University of Pittsburgh Cancer Institute and Medical Center; Grant No. U01-CA069853 from the Institute for Drug Development, Cancer Therapy, and Research Center, University of Texas Health Science Center; Grant No. CA62502 from Case Western Reserve University; Grant No. U01 -CA62505 from the City of Hope National Medical Center; Grant No. 5U0-1CA062487-14 from Wayne State University; Grant Nos. UO1-CA062491and NIH/GCRC M01 RR03186 from the University of Wisconsin; and Grant No. U01-CA76642 from New York University. Sponsored by the Cancer Therapy and Evaluation Program of the National Cancer Institute, Bethesda, MD. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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) 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. 
