Assessment of Hepatic Impairment and Implications for Pharmacokinetics of Substance Use Treatment

Abstract

While the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver’s pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the United States Food and Drug Administration (US FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range. A variety of noninvasive indices and radiologic procedures can be employed to assess hepatic drug metabolism and excretion. The Child-Pugh score is the most commonly used scale for assessing hepatic impairment among drugs submitted for US FDA approval. The score, originally developed to guide operative mortality in patients undergoing hepatic resection, has not been modified since its inception five decades ago. Furthermore, the score was not originally intended to be a guide for potential dose modification in patients with hepatic impairment. These reasons, in combination with the availability of a variety of new imaging modalities and an enhanced understanding of hepatic biology, should foster the development of novel methods to assess the effect of hepatic impairment on liver drug metabolism.

Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

“…to factors affecting the ability of the drug to enter the hepatocyte, rather than drug metabolism per se. 17,18 HCC and hepatic metastases do not have the same effect on general hepatocyte permeability that is seen in global hepatic impairment (e.g. related to cirrhosis or fibrosis).…”

“…related to cirrhosis or fibrosis). Since the liver has a very large capacity for drug metabolism, a reduction in the amount of healthy functioning liver (due to the presence of carcinoma/metastases) would not necessarily have any impact on drug clearance 17,18 . The aim of this study was to determine the exposure of olaparib in patients with globally impaired hepatic function, and therefore Child–Pugh criteria were determined to be the most appropriate classification to use to determine the degree of impairment for an individual patient.…”

Toward precision prescribing for methadone: Determinants of methadone deposition

“…We assessed fibrosis utilizing VCTE to assess liver stiffness, a surrogate for liver fibrosis, and the continuous attenuation parameter, a measure of hepatic steatosis. Cirrhosis reduces hepatic medication metabolism, and we sought to utilize VCTE as a method to assess the effect of hepatic insufficiency on drug metabolism [66]. As expected, a higher percentage of those with HCV infection had at least moderate fibrosis (>F2) compared to the uninfected participants.…”

Pharmacological pain management in patients with chronic hepatic disease

“…In patients with severe hepatic dysfunction, due to increased half-life and hypoalbuminemia an increase in the biological effects has been observed, and numerous side effects are also under discussion (20,21). Dose reduction is required (22). 4.…”