Design and conduct considerations for studies in patients with hepatic impairment

Abstract

Despite the liver being the primary site for clearance of xenobiotics utilizing a myriad of mechanisms ranging from cytochrome P450 enzyme pathways, glucuronidation, and biliary excretion, there is a dearth of information available as to how the severity of hepatic impairment (HI) can alter drug absorption and disposition (i.e., pharmacokinetics [PK]) as well as their efficacy and safety or pharmacodynamics (PD). In general, regulatory agencies recommend conducting PK studies in subjects with HI when hepatic metabolism/excretion accounts for more than 20% of drug elimination or if the drug has a narrow therapeutic range. In this tutorial, we provide an overview of the global regulatory landscape, clinical measures for hepatic function assessment, methods to stage HI severity, and consequently the impact on labeling. In addition, we provide an in‐depth practical guidance for designing and conducting clinical trials for patients with HI and on the application of modeling and simulation strategies in lieu of dedicated trials for dosing recommendations in patients with HI.

Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug–drug interactions

“…164 For this reason, in addition to drug-drug interaction studies in healthy volunteers, regulatory agencies recommend conducting PK studies in patients with hepatic impairment when the liver is involved in the metabolism or elimination of >20% of the drug or if the drug has a narrow therapeutic range. 167 Although the toxicity of some frequently used drugs is well known, often healthcare professionals and drug developers may not be fully aware of the effects that some drugs can have in patients with advanced liver injury. In these patients, who often receive multiple drugs, carefully planned drug prescribing, drug dose adjustments, and close monitoring of clinical outcomes are necessary.…”

“…Generally, regulatory agencies are concerned with the relatively high percentage of adverse drug reactions due to drug–drug interactions 164 . For this reason, in addition to drug–drug interaction studies in healthy volunteers, regulatory agencies recommend conducting PK studies in patients with hepatic impairment when the liver is involved in the metabolism or elimination of >20% of the drug or if the drug has a narrow therapeutic range 167 . Although the toxicity of some frequently used drugs is well known, often healthcare professionals and drug developers may not be fully aware of the effects that some drugs can have in patients with advanced liver injury.…”

Pharmacokinetics, safety, and tolerability of BMS‐986263, a lipid nanoparticle containing HSP47 siRNA, in participants with hepatic impairment

“…Each group included at least two female participants. Matching criteria using age, weight, and gender are consistent with the FDA and EMA guidance and published literature 12–14 . During part 2, eight participants with severe HI (group C) were enrolled in a staggered fashion after evaluation of the PK and safety results from participants with mild and moderate HI.…”

Pharmacokinetics of JNJ‐73763989 and JNJ‐56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment

“…The potential impact of hepatic impairment on the pharmacokinetics and safety of these drugs must be evaluated. Small single‐dose studies are often conducted first before exposing a larger population to multiple doses 15 …”

“…Small single-dose studies are often conducted first before exposing a larger population to multiple doses. 15 The purpose of the 2 studies was to assess the singledose pharmacokinetics, safety, and tolerability of JNJ-73763989 (73763989HPB1002, NCT04208386) or JNJ-56136379 (56136379HPB1009, NCT01208399) in participants with moderate hepatic impairment (Child-Pugh Class B), for reasons other than HBV infection, compared with healthy participants with normal liver function, matched for demographics (ie, sex, age, and body weight). Both studies were designed according to the US Food and Drug Administration (FDA) 16 and European Medicines Agency (EMA) 17 guidance on hepatic impairment.…”