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 C