Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)941-951
Number of pages11
JournalClinical Pharmacokinetics
Volume56
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Lorazepam
Status Epilepticus
Pharmacokinetics
Pediatrics
Population
Weights and Measures
Seizures
Software
Body Weight
Clinical Trials
Safety

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee (2017). Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. Clinical Pharmacokinetics, 56(8), 941-951. https://doi.org/10.1007/s40262-016-0486-0
on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. / Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. In: Clinical Pharmacokinetics. 2017 ; Vol. 56, No. 8. pp. 941-951.
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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.",
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on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee 2017, 'Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus', Clinical Pharmacokinetics, vol. 56, no. 8, pp. 941-951. https://doi.org/10.1007/s40262-016-0486-0

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. / on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

In: Clinical Pharmacokinetics, Vol. 56, No. 8, 01.08.2017, p. 941-951.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

AU - on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee

AU - Gonzalez, Daniel

AU - Chamberlain, James M.

AU - Guptill, Jeffrey T.

AU - Cohen-Wolkowiez, Michael

AU - Harper, Barrie

AU - Zhao, Jian

AU - Capparelli, Edmund V.

AU - Benjamin, Daniel K.

AU - Berezny, Katherine Y.

AU - Kearns, Gregory L.

AU - Laughon, Matthew M.

AU - Paul, Ian M.

AU - Smith, Michael J.

AU - Smith, P. Brian

AU - van den Anker, John

AU - Paul, Ian

AU - Siegel, David

AU - Taylor-Zapata, Perdita

AU - Zajicek, Anne

AU - Ren, Zhaoxia

AU - Tsilou, Ekaterini

AU - Pagan, Alice

AU - Anand, Ravinder

AU - Clemons, Traci

AU - Simone, Gina

AU - Cohen-Wolkowiez, Michael

AU - Watt, Kevin

AU - Guptill, Jeffrey T.

AU - Harper, Barrie

AU - Capparelli, Edmund V.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus. Clinical Pharmacokinetics. 2017 Aug 1;56(8):941-951. https://doi.org/10.1007/s40262-016-0486-0