Safe use of medication in patients with cirrhosis: pharmacokinetic and pharmacodynamic considerations

Abstract

Introduction: The global burden of cirrhosis is rising, and clinicians increasingly face the challenge of safely prescribing medicines for complications of hepatic disease and comorbidities. Prescribing in patients with cirrhosis is complicated by alterations that can occur in the pharmacology of medicines. Areas covered: This paper provides an overview of current knowledge on the pharmacokinetics and pharmacodynamics of medicines in patients with cirrhosis. We describe the pathophysiological changes that occur and their consequences on pharmacokinetic parameters. We explain that the influence of cirrhosis on the pharmacokinetics depends on several drug and patient characteristics. Patients with cirrhosis also have an increased susceptibility to some toxicological effects of medicines, such as renal impairment and hematological toxicity, which we describe in detail. In addition, we discuss approaches to apply this knowledge in practice and improve safe medication use in patients with cirrhosis. Expert opinion: Tailored pharmacotherapy is needed to ensure safe and appropriate use of medicines in patients with cirrhosis. Clinicians are supported by freely available recommendations on safe drug use in cirrhosis published on a website. In addition, a regular evaluation of medication use in patients with cirrhosis could resolve and prevent medication-related problems.

The pharmacokinetics of antibiotics in cystic fibrosis

“…displacing the binding sites of plasma proteins, and fluid retention [32]. Calculations of V d for ß-lactam antibiotics are discordant between older and newer studies.…”

“…Moreover, approximately 5-10% of CF patients develop cirrhosis during their first decade of life [31]. The presence of cirrhosis can cause lower plasma drug concentrations due to portal hypertensive gastropathy and impaired gastrointestinal motility, but more frequently leads to increased bioavailability due to a decreased first-pass effect [32]. Despite all these mechanisms oral bioavailability (the fraction of an administered drug that reaches the systemic circulation) seems largely unaffected.…”

Improving Medication‐Related Outcomes in Chronic Liver Disease

“…Overall, these PK alterations result in increased exposure (area under the plasma concentration time curve) to certain medications or metabolites. (32) Patients with cirrhosis are therefore at increased risk of ADRs, which may further contribute to intelligent nonadherence. Increased susceptibility to ADRs has been demonstrated in a prospective study of 1,280 patients.…”

“…(13) Patients may also have increased susceptibility to toxicologic effects of medications (PD change) due to existing disease complications, including thrombocytopenia (specific antibiotics, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]), impaired immunity (prednisolone, azathioprine), and renal impairment (diuretics, angiotensin therapies, NSAIDs). (32) With regard to susceptibility to hepatotoxicity, an increased risk of drug-induced liver injury (DILI) in CLD has only been evidenced in literature for some specific medicines (e.g., methotrexate, antituberculosis drugs, and antiretroviral therapy). (34)(35)(36)(37) Examples of clinically important PKPD changes in select medications (including PIMs) that occur in patients with cirrhosis are provided in Table 2.…”

Tivozanib in advanced inoperable hepatocellular carcinoma: considerations for patients with liver cirrhosis

“…In individual tivozanib exposure data suggested by the authors (supplement table 5), the maximum concentration for each patient was observed over a wide range which may have been due to different residual hepatic reservoir. Besides CYP3A4, several factors exist that may influence the PK/ PD profile, efficacy, and safety of TKIs in cirrhotic patients: portosystemic shunt, enterohepatic recirculation, biliary excretion, and drug reabsorption through gastrointestinal tract (21). In particular, in the case of patients with ascites (even in CTP class A6 cirrhosis), a portosystemic shunt with an increased hepatic venous pressure gradient resulted in the reduced first-pass metabolism of high-extraction ratio drugs and caused increased toxicity (22).…”