Antifungal Dosage Adjustment in Hepatic Failure

A number of antifungals require biotransformation into more water-soluble metabolites by the liver before excretion from the body. Antifungals are also known to have, like many other drugs, potentially toxic effects in the liver that may be enhanced with pre-existing liver disease. Therefore, antifungal therapy must be used in caution in patients with hepatic insufficiency. In terms of drug dosing, patients with moderate to severe hepatic dysfunction often exhibit a decreased capacity to metabolize certain antifungal agents, leading to decreased overall drug clearance, an increase in the plasma/serum area under the concentration curve (AUC), and prolongation of the half-life (t1/2) of the drug. Hepatic dysfunction can affect the pharmacokinetics and pharmacodynamics of antifungal agents by 1) Reducing the activity of drug metabolizing enzymes such as the cytochrome P450 system, 2) reducing the synthesis of plasma proteins to which the antifungals bind in the bloodstream, and 3) decreasing hepatic blood flow, which results in a decreased efficiency of the liver to clear drugs [1941].

Unfortunately, the severity of hepatic dysfunction and its consequent effects on drug therapy are much more difficult to quantify than renal dysfunction and no single test or calculation has been shown to satisfactorily measure hepatic function and its impairment. This is probably due to the wide spectrum of causes and clinical sequalae of liver dysfunction (e.g., cirrhosis, acute vs. chronic hepatitis, drug-induced liver disease). The most common severity index of hepatic dysfunction reported in the medical literature is the (E):Child-Pugh Score, which is determined from well described clinical indicators of hepatic function such as protein and coagulation status, and the presence and severity of ascites and/or encephalopathy. Based on the fundamental understanding of drug pharmacokinetics, general recommendations for dosage adjustment of antifungals in patients with hepatic dysfunction can be summarized below: