Pediatric Hepatic Impairment Dosing in FDA Approvals Between 2002 and 2024.

Abstract

The safety and efficacy of drugs metabolized by the liver can be substantially impacted by alterations in hepatic function. However, hepatic impairment (HI) is rarely evaluated in pediatric drug development due to challenges such as the relatively small number of patients, differences in adult and pediatric liver disease, and the lack of agreed-upon markers to assess HI severity. The objectives of the study were to (1) examine adult and pediatric HI dosing recommendations in US FDA prescribing information (PI) and pediatric dosing handbooks, Lexicomp and Micromedex, and (2) identify the clinical evidence behind HI dosing recommendations for pediatric patients. A total of 61 drugs containing both a pediatric indication and the word "hepatic" in the Dosage and Administration section of the PI were reviewed. Of the 61 drugs, only eight drugs included pediatric-specific HI dosing recommendations, with seven based on the Child-Pugh classification. Pharmacokinetic studies in adults with HI were the primary evidence behind the recommendations for all eight drugs, and only one drug was evaluated in pediatric patients with mild HI. Lexicomp and Micromedex provided consistent HI dosing recommendations with the PI and did not cite additional evidence. Overall, there is a gap in dosing recommendations for pediatric patients with HI. Alternative approaches, such as modeling and simulation based on drug- and disease-specific parameters, may help address knowledge gaps for pediatric patients with HI in the future.