Physiologically based pharmacokinetic model of brivaracetam to predict the exposure and dose exploration in hepatic impairment and elderly populations.

• This study is the first to develop a physiologically based pharmacokinetic (PBPK) model for brivaracetam (BRV) to predict exposure and explore dosing in hepatic impairment and elderly populations. It was used to describe the PK behavior of BRV in specific populations. • In this study, all known metabolic enzymes of BRV were fully considered and incorporated into our model. This allowed us to better characterize the absorption, distribution, metabolism and excretion characteristics (ADME) process of BRV. • The validated BRV PBPK model is combined with clinical practice to give different dosing regimens for specific patients to achieve safe and effective BRV concentrations. This can provide a reference for precise clinical dosing and clinical trials. Brivaracetam (BRV) is a new third-generation antiseizure medication for the treatment of focal epileptic seizures. Its use has been increasing among epileptic populations in recent years, but pharmacokinetic (PK) behavior may change in hepatic impairment and the elderly populations. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® to develop a physiologically based pharmacokinetic (PBPK) model for adults and extrapolate it to hepatic impairment and the elderly populations. The model was evaluated with clinical PK data, and dosage explorations were conducted. For the adult population with mild hepatic impairment, the dose is recommended to be adjusted to 70 % of the recommended dose, and to 60 % for moderate and severe hepatic impairment. For the elderly population with mild hepatic impairment under 80 years old, it is recommended that the dose be adjusted to 60 % of the recommended dose and to 50 % for moderate and severe conditions. The elderly population with hepatic impairment over 80 years old is adjusted to 50 % of the recommended dose for all stages. Healthy elderly do not need to adjust. The BRV PBPK model was successfully developed, studying exposure in hepatic impairment and elderly populations and optimizing dosing regimens. [ABSTRACT FROM AUTHOR]