Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

Abstract

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.

Figure 1

Diagnostic plots of final population pharmacokinetic model. Goodness‐of‐fit plots for the final model. (a) Observed vs. population. (b) Observed vs. individual predictions. (c) Conditional weighted residuals vs. population predictions. (d) Conditional weighted residuals vs. time in hours after first dose. For plots a and b, axes with concentration values are log scaled, the solid black line represents the line of unity, and the dotted black line represents a regression line. For plots c and d, the solid black line represents the locally weighted scatterplot smoothing curve, and reference lines of y = 0 and ± 2, and ± 4 are provided.

Figure 2

Visual predictive check for the final population pharmacokinetic model based on 1,000 simulations. The open circles represent the observed data, the dashed and solid lines represent the 5th, 50th, and 95th percentiles for the observed and simulated data, respectively. The shaded region represents the 90% prediction interval based on 1,000 simulations.

Figure 3

Results from Monte Carlo simulations of a single diazepam dose. Predicted diazepam concentrations at 10 minutes after a single i.v. dose in simulated patients. Study dose: 0.2 mg/kg (maximum 8 mg); product label high dose: 0.5 mg in children 31 days to < 5 years old and 1 mg in children ≥ 5 years; product label low dose: 0.2 mg in children 31 days to < 5 years old and 1 mg in children ≥ 5 years. Horizontal dotted lines indicate the commonly accepted target therapeutic range of 200–600 ng/mL.