Affiliation:
1. 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....
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 × 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.
Publisher
American Society of Clinical Oncology (ASCO)
Reference31 articles.
1. Buchdunger E, Zimmermann J, Mett H, et al: Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56: 100,1996-104,
2. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells
3. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: 139,2000-145,
4. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor
5. Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
Cited by
86 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献