Dose Adaptation of Antineoplastic Drugs in Patients with Liver Disease

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 metabolism in patients with impaired liver function to allow quantitative advice to be given for dose adaptation.

Outcomes in Lymphoma Patients with Obstructive Jaundice: A Cancer Center Experience

“…Some physicians may argue that procedural intervention for biliary decompression is not necessary in lymphoma patients who present with obstructive jaundice because chemotherapy will lead to rapid resolution of the biliary obstruction [23]. However, administering chemotherapy to lymphoma patients with obstructive jaundice may enhance the risk profile of many chemotherapeutic agents particularly those with high hepatic extraction like doxorubicin and vinblastine [5]. While the risk reward profile of biliary decompression in this setting is not well defined, our institutional bias is to favor early decompression.…”

“…In the United States, lymphoma accounts for 5% of new cancer cases and 3.6% of cancer deaths annually. Obstructive jaundice, a rare complication of lymphoma, can accompany the initial presentation of lymphoma or develop later in the course of the disease [5]. Obstructive jaundice can also indicate recurrent disease in a patient with a history of lymphoma.…”

“…However, little published information is available to guide clinicians on the effective management of obstructive jaundice in lymphoma patients. As hyperbilirubinemia can potentiate the hepatotoxicity of chemotherapy [5,6], our institutional approach is to perform biliary stent placement by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous biliary decompression (PBD) when chemotherapy is initiated. Given the chemoresponsiveness of many lymphomas, our interventional approach to obstructive jaundice in lymphoma patients differs from that of obstructive jaundice in patients with hepatobiliary or pancreatic malignancies [7].…”

Preparative Regimen Dosing for Hematopoietic Stem Cell Transplantation in Patients with Chronic Hepatic Impairment: Analysis of the Literature and Recommendations

“…Patients with greater transaminase elevations before HSCT were reported to have a higher incidence of severe SOS than those with minimal elevations [7]. Several other prospective studies have also reported an association between pretransplant transaminase elevations and subsequent development of SOS [9,10,12]. These studies also reported a marginal statistical significance for correlation between severe SOS and a remote history of hepatitis, drug-related liver injury, or abdominal radiation therapy [7].…”

“…However, the literature consists of mostly case reports including patients with only moderate liver dysfunction. In addition, administration guidelines have focused on patients with liver cirrhosis or fibrosis and not on patients with increased transaminases and/or cholestasis [12]. Therefore, the available pharmacokinetic data are far from complete.…”