Special Populations: Hepatic Impairment

Abstract

PURPOSE AND RATIONALE Liver and kidney are the main organs involved in the elimination of drugs. Both have a metabolic and a direct excretory capacity, but liver is generally the main organ responsible for drug metabolism and also metabolite excretion. Direct biliary excretion occurs also, but is some-times a futile pathway because of enterohepatic cycling (reabsorption). Because of a variety of processes involved in drug elimination by the liver, liver disease can affect the pharmacokinetics by several mechanisms, for instance, re-duced metabolic enzyme activity (Frye et al. 2006), altered hepatic uptake or biliary excretion by transporters and more generally reduced liver blood flow (Verbeeck 2008). Major plasma proteins are synthesized by the liver and drug pharmacokinetics can be affected by decreased plasma protein binding. Liver disease can also affect other organs such as the kidney. Both the FDA (2003) and EMEA CHMP (2005) have issued quite similar guidances for studies on the effect of hepatic impairment. For a new drug candidate the effect should be studied if the drug is likely to be administered in patients with hepatic impairment, if the condition is likely to affect the PK of the drug and if in that case it would be necessary to proceed with a dose-adjustment in such pati-ents. The FDA recommends a study to be performed if the liver contributes for more than 20% in the elimination of the parent drug or an active metabolite and for any drug with a narrow therapeutic range. An exception is made for drugs intended for single-dose administration. Moreover, for drugs with a high hepatic extraction ratio (>70%) and high plasma protein binding (>90%) the unbound drug pharmacokinetics should also be evaluated. In some cases the total drug concentration can mask an effect on the unbound drug concentration (see also chapter on protein binding considerations). In contrast to renal impairment, and maybe because there are several mechanisms potentially involved in the effect of liver dysfunction on drug pharmacokinetics, it has proven difficult to find an adequate marker to classify liver disease with a good predictive value. Both guidances recommend the Child-Pugh score as the preferred classification system, acknowledging its limita-tions and the need for further exploration. The Child-Pugh score is a composite of five parameters, three biochemical (serum albumin, serum bilirubin, prothrom-bin time) and two clinical (encephalopathy and ascites) (> Table B.8-1). The classification is A or mild hepatic impairment for a score of 5–6 points, B or moderate for a score of 7–9 and C or severe for 10 and more. It is important to apply this score only for patients diagnosed with liver disease, because a score of 5 is the minimum value, even in the absence of any abnorma-lities. On the other hand, some parameters can also be changed in other clinical conditions. Even in patients with liver disease, the underlying condition can also affect the pharmacokinetics of drugs differently (e.g., alcoholic cir-rhosis, cholestasis, viral hepatitis, liver metastases). There are different approaches to study the effect of hepatic impairment on drug elimination. One approach is a population PK screen in large scale clinical trials, which allows to compare patients with liver disease with the typ-ical patient population in the proposed indication. Some limitations of this approach are that it does not address patients that are voluntary excluded from such studies, which is generally the case for severe and sometimes also moderate hepatic impairment. Also, some specific param-eters like unbound drug fraction and circulating metabo-lites may need to be included in the evaluation and the sample size should provide sufficient sensitivity. However, the approach may be very useful to confirm the absence of a risk of liver impairment, or to investigate the effect when it is not feasible to conduct a specific study in subjects with-out potential clinical benefit, for instance anticancer drugs (Bruno et al. 1998). In case of a risk, an alternative appro-ach can be a dose-escalation study in patients with liver dysfunction (Raymond et al. 2002). When a specific hepatic impairment study is conducted this can be done according to a full design or a reduced design. In the first case all relevant degrees of hepatic impairment are included in the study. In the reduced design only the worst case is initially evaluated in comparison to normal subjects. If necessary, the study can be completed