Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Abstract

Background: Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE.

Methods: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations.

Results: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)^0.133*WT^0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT^0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control.

Conclusions: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

Figure 1

Observations versus population and individual predictions from the final population pharmacokinetic model. The dashed lines represent the line of unity and the loess curve.

Figure 2

Conditional weighted residuals (CWRES) versus time after dose and population predictions for the final population pharmacokinetic model. The dashed black lines represent the line at which the CWRES is equal to zero and the loess curve. The solid grey lines represent the CWRES values of 2 and −2.

Figure 3

Visual predictive check for final population pharmacokinetic model stratified by postnatal age. 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 grey region represents the 90% prediction interval. One thousand simulations were performed.

Figure 4

Clearance (top), steady-state volume of distribution (middle), and predicted concentration at 10 min (C₁₀ lower) versus outcomes. The box is the interquartile range, and the whiskers represent the 5th and 95th percentiles.