Effect of liver disease on dose optimization

Abstract

Many narrow therapeutic index drugs are eliminated primarily by hepatic metabolism. Selecting the proper dosing regimen for such drugs in the presence of liver disease is an important therapeutic problem. However, the effect of liver diseases on drug disposition is complex, and depends on the pathophysiology of the disease and the pharmacokinetic characteristics of the drug itself. Hepatic clearance concepts provide a general framework for understanding and predicting the changes in pharmacokinetics of drugs with high and low intrinsic clearances, but this approach is not sufficiently robust for clinical use due to difficulties in measuring patient-specific hepatocellular function and hepatic blood flow. Further complicating the ability to predict hepatic clearance in the presence of liver disease is that hepatic enzymes may be differentially affected by the presence of liver disease-glucuronidation is well-preserved even in advanced liver disease, and mild to moderate liver disease has selective effects on the catalytic activity of specific cytochrome P450 metabolizing enzymes, with CYP2C19 more sensitive to liver disease than CYP2D6. Despite considerable efforts to develop non-invasive probes of hepatic metabolic activity, there are still none that are useful clinically. Therapeutic drug monitoring may have some value, but is limited by changes in plasma protein binding that are common in liver disease. More studies are needed to develop better probes, and, in the drug development process, to provide better information on metabolic pathways and laboratory and clinical covariates that can be used to individualize dosing regimens in the presence of coexisting diseases and concurrent drug therapy.