The liver is a major organ involved in the clearance of drugs via a variety of mechanisms and pathways (e.g., cytochrome P450 [CYP] enzyme pathways, glucuronidation, biliary excretion) and hepatic impairment/dysfunction/disease can alter the clearance of drugs. As such, patients with hepatic disease may require modification to their dosing regimen for a given drug relative to patients with normal hepatic function. The impact of hepatic impairment on a drug’s disposition, clearance, and metabolism is assessed by pharmacokinetics.
In general, an assessment of pharmacokinetics in subjects with hepatic impairment is needed if a drug’s hepatic metabolism and/or excretion accounts for >20% of the elimination of a parent drug or active metabolite. Also, hepatic impairment investigations are typically needed in an NDA submission for drugs with a narrow therapeutic range or if the routes of metabolism and excretion of a drug are unknown.
There are exceptions to consider when determining the proper strategy for evaluating how hepatic impairment PK data should be collected; for example, should a drug be evaluated via a standalone hepatic impairment study or within the context of late phase studies (i.e., using a population PK/sparse sampling approach in a patient population enriched with varying degrees of hepatic disease)? There are also a number of drugs for which a standalone hepatic impairment study is not necessary or required.
Scientific & PK Considerations
Full PK Study Design
The FDA’s guidance to industry suggests that a full PK study can be conducted in patients from the three Child-Pugh categories of impaired hepatic function: mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C), as well as matched controls (i.e., matched to age, weight, and gender). However, enrolling severe patients from Child-Pugh class C can be difficult and time consuming and Nuventra has clinical and regulatory strategies for efficiently executing this type of study. The overall goal is to determine whether the PK and/or PD of a drug and its active metabolites are altered in patients with hepatic impairment.
Reduced PK Study Design
In a reduced PK study design, only subjects with moderate hepatic impairment (Child-Pugh class B) are enrolled and compared to matched healthy volunteers. At least 8 evaluable subjects each from moderate impairment and control groups should be enrolled for the reduced PK study but statistical power calculations may be needed depending on the anticipated variability in the pharmacokinetics of the drug.
The reduced and full PK study designs can be conducted either as single dose or multiple dose studies depending on the expected pharmacokinetic behavior of the drug. Also, dose strength must be considered in these studies since impaired hepatic function might lead to higher exposures and safety concerns for the study population. As such, a unique PK plasma sampling schedule for the different levels of hepatic impairment might need to be considered. An experienced pharmacokineticist can quickly and efficiently determine if any dose adjustments are needed in a hepatic impairment study and also advise on frequency of plasma sample collection to enable a robust assessment of pharmacokinetics. A clinical pharmacology consultant can assist with development of the overall design of the impaired hepatic function study.
Population PK Analyses
Population PK analysis is be conducted with sparse sampling of drug concentrations from patients enrolled in late stage studies. The studies need to be enriched for patients with varying degrees of hepatic impairment to enable population PK analyses and modeling of the relationship between Child-Pugh score and PK parameters such as AUC, Cmax, apparent clearance (CL/F), apparent volume of distribution (V/F), terminal half-life (t1/2), and more. The sponsor must take care to capture individual components of the Child-Pugh score (encephalopathy, ascites, serum bilirubin, serum albumin, and prothrombin time) to enable robust population PK.
Nuventra has significant experience in studies of patients with liver disease and hepatic encephalopathy combined with significant pharmacokinetic experience to enable a successful study and population PK analysis.
When to Executive Hepatic Studies in Development Programs
Whether a full or reduced hepatic impairment study should be conducted depends on a number of factors including in vitro CYP P450 inhibition/induction assays and the potential for the investigational drug to have altered PK in patients with hepatic impairment. If a drug has a low potential for altered pharmacokinetics with hepatic impairment or will never be used in patients with severe hepatic disease then a reduced study design in moderate hepatic disease may be more appropriate. Alternatively, if the late stage studies will be enriched for varying degrees of hepatic dysfunction then population PK analyses could be conducted, which may be more cost effective relative to standalone PK studies in hepatically impaired subjects.
Read more in the FDA Guidance “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”