FDA drafts guidance on assessing impact of hepatic impairment on drug PK/PD
The US Food and Drug Administration (FDA) has published a draft guidance on how to design trials and analyze data from studies examining the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs in patients with hepatic impairment (HI). The agency noted that impaired liver function can have a significant impact on how drugs are absorbed and filtered, requiring a better understanding of their effects.
On 1 September, FDA published the draft guidance that outlines when studies should be conducted to assess the effects of HI on the pharmacokinetics or pharmacodynamics of a drug or when it may not be necessary. It also outlined how to design and conduct studies to understand the effects of HI on a drug's pharmacokinetics, and how to analyze the resulting data.
FDA explained that the liver plays an important function in filtering drugs through metabolism and/or biliary excretion of unchanged drugs or their metabolites. As a result, it said it published the guidance to understand the effect of HI on drug pharmacokinetics and pharmacodynamics, as liver disease can significantly affect metabolic and excretory pathways by altering drug-metabolizing enzymes and transporters, as well as how drugs are absorbed and distributed in the body.
"Liver disease can also alter the pharmacodynamic effects of a drug, potentially affecting safety (e.g., increased sedation if patients with hepatic encephalopathy are treated with benzodiazepines; impaired synthesis of coagulation factors in patients with cirrhosis may increase the bleeding risk of direct-acting oral anticoagulants)," said FDA. "Liver disease can also alter kidney function (e.g., hepatorenal syndrome), potentially leading to changes in the pharmacokinetics of a drug and its metabolites even when the liver is not primarily responsible for their elimination.
"The specific impact of various phenotypes of liver disease (e.g., hepatocellular vs. cholestatic, acute vs. chronic) on hepatic function is still not completely understood, making it challenging to predict the effects of different phenotypes of liver disease on the pharmacokinetics and pharmacodynamics of a drug," the agency added.
FDA noted that patients with HI have often been excluded from clinical trials, even in instances where the drug was specifically developed for them. The agency said that understanding the effects of HI on pharmacokinetics early in the drug development process may allow researchers to include such patients in trials and better understand the drugs' effects on the target population.
The guidance lists situations when sponsors should consider conducting a pharmacokinetic study in patients with HI, including in situations when hepatic metabolism and/or excretion accounts for more than 30 percent of the elimination of absorbed parent drug or active metabolites, when minimal drug concentrations may significantly impact the safety and effectiveness of the drug, there's a lack of understanding about the elimination pathways of the drug, the drug is intended to treat patient with liver disease, and when it is likely to be used in patients with HI.
On the contrary, the guidance also lists circumstances in which a dedicated pharmacokinetic study may not be necessary, including when hepatic metabolism and/or excretion are minimal, and drug concentration changes do not significantly affect safety and effectiveness. Furthermore, such studies are unnecessary when the drug is excreted entirely via the renal route without liver involved, is intended for a single administration, acts locally, or is primarily eliminated via the lungs.
"The effect of HI should be assessed early in drug development to adequately guide trial eligibility and identify a recommended dosage for patients with HI," said FDA. "In the case of orphan drugs, where the population with the disease is fewer than 200,000, sponsors should reach out to the appropriate FDA review division early during drug development to discuss the timing and characterization of the pharmacokinetics of a drug in subjects with HI."
The guidance also lists study design considerations such as how to assess hepatic function, how to design a dedicated pharmacokinetic study, considerations for pharmacodynamic assessments, and, alternatively, how to use a population pharmacokinetic (popPK) approach.
"If subjects with varying degrees of HI are adequately represented in clinical trials (see section 311 IV.A. Assessment of Hepatic Function), and there are sufficient drug concentration data to describe the pharmacokinetics of the drug, popPK analyses of data from clinical trials could be sufficient to characterize the impact of HI on drug exposure for the population represented in the trials," said FDA. "If subjects with HI cannot be enrolled in sufficient numbers, a dedicated HI pharmacokinetic study may be conducted to support appropriate dosage for the HI population not represented in clinical trials."
The guidance details how to analyze study data to understand the pharmacokinetic and pharmacodynamic effects of drugs in people with HI. More specifically, it details how to estimate parameters and convey study results, analyze the relationship between measures of hepatic function and pharmacokinetics, and develop dosage recommendations. It also details how sponsors should include labeling that summarizes essential scientific information to help HI patients understand the safety and effectiveness of the drugs.
