The effects of liver disease on the pharmacokinetics of a drug should be investigated if hepatic metabolism or excretion contributes to a substantial part of the total elimination and/or if an active metabolite is formed or eliminated by the liver. In addition, studies may be considered if the drug is extensively protein-bound or if it has a narrow therapeutic range. The main objective of a hepatic impairment study is to identify patients at risk and, when appropriate, to develop dosing recommendations in the patients with hepatic disease.
The effect of liver disease on the pharmacokinetics of a drug is usually investigated in cirrhotic volunteers. The diagnosis should, if possible, be established by biopsies. The group of cirrhotic volunteers should generally cover the whole range of metabolic impairment. A control group should be included representing the target population with respect to demographic factors. The hepatic function groups should be comparable with respect to age, gender, weight, and other factors with significant potential to affect the pharmacokinetics. The use of historical controls instead of including controls with normal liver function is not recommended as, due to interstudy variability, this may mask a difference in pharmacokinetics of the drug. The number of volunteers or patients included should be sufficient to detect clinically relevant pharmacokinetic differences.
Patients classified by the Child-Pugh system as having mild impairment could have a normal hepatic function and for the majority of drugs, clinically significant differences are more likely to be observed in patients with moderate and severe impairment. Thus, a reduced design including only patients with moderate impairment and controls may be used to screen for significant effects. If a significant effect is detected in the moderate group, the pharmacokinetics in patients with mild impairment needs to be evaluated to propose dose recommendations for this group.
An alternative way of assessing the effect of liver disease on the pharmacokinetics of a drug is to use population pharmacokinetic data obtained in phase II and III studies as has been described for renal impairment. However, this approach may prove more difficult here due to e.g., lower prevalence of hepatic impairment in the general population. In these studies, patients with hepatic impairment should be identified and classified using the same criteria as has been discussed for the conventional studies. Population analysis for this purpose should be prespecified.
For prodrugs (i.e., drugs with activity predominantly due to hepatically generated metabolite), it is possible that the dose may need to be increased, or the dosing interval shortened, in hepatically impaired patients.
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