Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity.

Abstract

Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing. Diazepam concentrations after IV or oral administration for 61 children aged 2.5 to 20.6 years were used to externally evaluate the model including the addition of fixed oral absorption parameters. Then, PK parameters were re-estimated with the external population alone and again in combination with the original population. Re-estimated parameters from the combined population were used to simulate recommended dosing for children with and without obesity. The external dataset included 88 plasma concentrations from 61 children (54 with obesity) receiving diazepam per standard of care. The external evaluation resulted in 34.5% of predicted values within 30% of the observed concentration. Parameter re-estimation resulted in increased central volume of distribution (26% increase from a previous model), reduced peripheral volume of distribution and intercompartmental clearance, and similar clearance estimates. Simulations demonstrated that dosing caps may prevent children with obesity from reaching the suggested target exposure that is recommended for the treatment of status epilepticus. Further study is needed to evaluate the target exposure range in this population.