Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments

Abstract

The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, such as Cmax/MIC, AUC/MIC, T>MIC, IC50/EC50, or T>EC95. Loss of efficacy, or conversely, increased risk of toxicity may occur in certain circumstances of liver injury. Although important to consider these potential alterations and their effects on specific anti-infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy.

Metabolomic Profile of Primary Turkey and Rat Hepatocytes and Two Cell Lines after Chloramphenicol Exposure

“…Only trace amounts of nontoxic CAP-G were detected in the HepG2 cell cultures. This result may confirm the kinetics of the drug in patients with liver cancer [11]. No metabolites were found in the Balb/c 3T3 fibroblast cultures.…”

“…The use of CAP in humans can lead to serious hematologic and metabolic toxicity (e.g., "gray baby syndrome" in newborns and young infants) [1,2]. The drug is metabolized primarily in the liver [10] and its use by patients with liver cancer may pose a risk of adverse drug reaction [11]. Additionally, the drug shows toxicity to the liver and reproductive system in animals [2].…”

Pharmacokinetic/Pharmacodynamic Modelling and Simulation of Lusutrombopag, a Novel Thrombopoietin Receptor Agonist, for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures

“…The median AUC in patients with Child–Pugh class C was lower than that in patients with Child–Pugh class A or B. Patients with hepatic impairment may have intestinal structural alterations that decrease the extent of drug absorption [22]. The individual peak platelet counts overlapped among the Child–Pugh classes, although the sample size was limited for patients with Child–Pugh class C ( n = 6).…”

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

“…However, other laboratory markers may be associated with altered drug exposure. For instance, due to chemotherapy, concomitant medications can cause liver function disorders which affect the pharmacokinetic processes like absorption, distribution, elimination, metabolism, which can lead to changes in posaconazole exposure. Analysing potential effect of routine laboratory markers can help defining the appropriate population for TDM of posaconazole.…”