Variations of pharmacokinetics of drugs in patients with cirrhosis

ABSTRACT

Liver cirrhosis is the end stage of many different chronic liver diseases and is becoming an important cause of mortality and morbidity across the world. In theory, the numerous physiopathological changes suffered by these patients warrant relevant pharmacokinetic changes in most drugs. However, the influence of these changes on the efficacy and toxicity responses of patients with cirrhosis have been evaluated by few clinical trials and observational studies. As a consequence, therapeutic decisions in these patients are usually complex and subject to uncertainties. In this article, we review the regulatory guidelines to study responses to drugs according to pharmacokinetic variability and the published information that is useful for guiding the dosage adjustment of frequently used drugs in patients with cirrhosis (antivirals, antibiotics, analgesics, etc.) to obtain the best risk-benefit ratio.

KEYWORDS:

• Cirrhosis
• pharmacokinetics
• variability
• clinical Trials
• antivirals
• antibiotics
• analgesics

Financial and competing interests disclosure

The authors work was supported in part by a grant from Instituto de Salud Carlos III, Madrid, Spain (Grant Code: PI14/01090). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Liver cirrhosis is an important cause of variability in drug response due to the central role of the liver in the pharmacokinetics of most drugs.

• Guidelines recommend starting drug treatment at lower effective doses and performing a continuous assessment of the risk–benefit relationship in patients with liver cirrhosis.

• On the basis of the following equation, Cl_H = Q_H × E_H = (Q_H × fp × Cl_int)/(Q_H + fp × Cl_int) [where: Q_H is the hepatic blood flow; E_H is the hepatic extraction ratio, which depends on liver blood flow (Q_H), intrinsic clearance of unbound drug (Cl_int) and unbound fraction in the blood (fp)], drugs can be categorized according to the E_H into three categories: highly extracted drugs (E_H > 0.7), drugs with intermediate extraction (0.3 < E_H < 0.7), and drugs with low extraction (E_H < 0.3).

• Drugs with a high hepatic extraction ratio (E_H > 0.7) show a clearance that is dependent on blood flow and is insensitive to changes in binding to blood components or enzyme/transporter activity. No dosing change is needed when protein binding is reduced.

• Drugs with a low hepatic extraction ratio (E_H < 0.3) are influenced by both changes in blood/plasma binding and enzyme/transporter activity, and the influence of hepatic disease on clearance is less predictable. Dosing change is needed when protein binding is reduced.

• Currently, guidelines recommend using the Child–Pugh classification to categorize hepatic impairment in clinical trials, but this score is not directly associated with pharmacokinetic changes.

• Chronic hepatitis C treatment: No dose adjustment is required in patients with cirrhosis treated with sofosbuvir, daclatasvir, ledipasvir, and ombitasvir.

• Chronic hepatitis B treatment: No dose adjustment is required in patients with cirrhosis treated with lamivudine, adefovir, entecavir, telvibudine, and tenofovir.

• There are few studies that have examined the effect of liver disease on antiretroviral drug pharmacokinetics.

• Dosage reduction is determined empirically in most patients with cirrhosis treated with antibiotics.

• Paracetamol may be considered a good analgesic in liver cirrhosis if overdose risk can be disregarded.