Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

摘要

The liver is a complex organ with great ability to influence drug pharmacokinetics (PK). Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, the effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what effects these changes will have on a particular drug. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling PK/pharmacodynamic targets, such as maximum concentration/minimum inhibitory concentration (Cmax/MIC), area under the curve/minimum inhibitory concentration (AUC/MIC), time above MIC (TMIC), half-maximal inhibitory concentration (IC50) or half-maximal effective concentration (EC50), or the time above the concentration which inhibits viral replication by 95% (TEC95). Loss of efficacy and/or an increased risk of toxicity may occur in certain circumstances of liver injury. Although it is important to consider these potential alterations and their effects on specific anti-infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy.