Dose Adaptation of Antineoplastic Drugs in Patients with Liver Disease
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Drug Safety 2006; 29 (6): 509-522 0114-5916/06/0006-0509/$39.95/0 2006 Adis Data Information BV. All rights reserved.
Dose Adaptation of Antineoplastic Drugs in Patients with Liver Disease ˆ 1 Peter Wolf2 and Lydia Tchambaz,1 Chantal Schlatter,1 Max Jakob,1 Anita Krˆahenbuhl, 1 ˆ Stephan Krˆahenbuhl 1 2
Division of Clinical Pharmacology & Toxicology, University Hopsital, Basel, Switzerland Hospital Library, University Hospital, Basel, Switzerland
Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 2. Literature Search Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 3. Literature Search Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
Abstract
Dose adaptation for liver disease is important in patients treated with antineoplastic drugs because of the high prevalence of impaired liver function in this population and the dose-dependent, frequently serious adverse effects of these drugs. We classified the antineoplastic drugs marketed in Switzerland at the end of 2004 according to their bioavailability and/or hepatic extraction to predict their kinetic behaviour in patients with decreased liver function. This prediction was compared with kinetic studies carried out with these drugs in patients with liver disease. The studies were identified by a structured, computer-based literature search. Of the 69 drugs identified, 52 had a predominant extrarenal (in most cases hepatic) metabolism and/or excretion. For 49 drugs, hepatic extraction could be calculated and/or bioavailability data were available, allowing classification according to hepatic extraction. For 18 drugs, kinetic studies have been reported in patients with impaired liver function, with the findings generally resulting in quantitative recommendations for adaptation of the dosage. In particular, recommendations are precise for 16 drugs excreted by the bile (e.g. doxorubicin and derivatives and vinca alkaloids). Validation studies comparing such recommendations with kinetics and/or dynamics of antineoplastic drugs in patients with decreased liver function have not been published. We conclude that there are currently not enough data for safe use of cyctostatics in patients with liver disease. Pharmaceutical companies should be urged to provide kinetic data (especially hepatic extraction data) for the classification of such drugs and to conduct kinetic studies for drugs with primarily hepatic metaboli
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