Physiologically based pharmacokinetic modeling of diazepam: quantitative assessment of hepatic impairment and model-informed dose optimization in patients with liver cirrhosis.

Diazepam is a widely prescribed benzodiazepine that undergoes extensive hepatic metabolism. Patients with liver cirrhosis may exhibit altered diazepam pharmacokinetics (PK), resulting in increased systemic exposure and a higher risk of adverse effects. This study aimed to develop a physiologically-based-pharmacokinetic (PBPK) model of diazepam and evaluate the impact of hepatic impairment on drug exposure and dose requirements. A PBPK model of diazepam was developed using PK-Sim® based on published clinical PK data from healthy subjects. Drug-specific physicochemical and metabolic parameters were incorporated into the model. The model was externally qualified using independent intravenous and oral clinical datasets. Subsequently, disease-specific physiological and biochemical changes associated with Child-Pugh A (CP-A) and Child-Pugh B (CP-B) liver cirrhosis were incorporated to establish hepatic impairment PBPK models. Model-based simulations were performed to assess PK alterations and optimize dosing strategies. The developed PBPK model adequately described diazepam plasma concentration-time profiles across multiple dosing regimens and administration routes. All predicted-to-observed ratios for AUC and Cmax were within the predefined twofold error range. Simulations demonstrated progressive increases in diazepam exposure with worsening hepatic impairment. Following repeated oral administration of 5 mg twice daily, predicted steady-state AUC increased by 43.6% and 72.6% in CP-A and CP-B patients, respectively, compared with healthy subjects. Model-based extrapolation and dose optimization indicated that dose reductions of approximately 30% for CP-A and 42% for CP-B patients were required to achieve exposure comparable to that observed in healthy individuals. Sensitivity analysis identified CYP3A4-mediated metabolism, liver volume, plasma protein binding, and fraction unbound as key determinants of diazepam PKs. The developed PBPK model characterized diazepam PKs in healthy subjects and provided a disease-extrapolation framework for patients with liver cirrhosis. The model provides a quantitative framework for predicting hepatic impairment-associated PK changes and supports rational dose adjustment of diazepam according to the severity of liver dysfunction.