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Clinical Trial
. 2017 Aug;56(8):941-951.
doi: 10.1007/s40262-016-0486-0.

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Collaborators, Affiliations
Free PMC article
Clinical Trial

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Daniel Gonzalez et al. Clin Pharmacokinet. .
Free PMC article

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*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. 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.

Conflict of interest statement

Compliance with Ethical Standards

Funding and Conflicts of Interest: This work was funded under National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I (PI: Benjamin) for the Pediatric Trials Network. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001117. D.G. receives support for research from NICHD (K23HD083465), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), and from industry (Cempra, Inc. and Jacobus Pharmaceutical Company, Inc.) for drug development in adults and children. M.C.-W. receives support for research from the NIH (1R01-HD076676-01A1), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Allergy and Infectious Disease (NIAID) (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (BARDA) (HHSO100201300009C), and the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org) for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). J.T.G. receives research support through K23NS085049 from the National Institute of Neurological Disorders and Stroke (NINDS). The remaining authors have no funding to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Ethical approval: Both pediatric studies were reviewed and approved by local institutional review boards.

Informed consent: For the Status 1 study, patients either pre-consented to participate in the study prior to presentation of SE or consented to participate in the study after they received lorazepam if they presented to the emergency department in SE. For Status 2 study, participating hospitals submitted a site-specific plan to their institutional review board regarding the specific activities to address the requirements for the Exception from Informed Consent for Emergency Research (21 CFR 50.24). Thus, patients were treated prior to consent and then once their condition had stabilized the family was approached to discuss the study and obtain written consent for continued study participation.

Figures

Figure 1
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
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
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
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.

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