Dataset Information

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.

SUBMITTER: Ku LC

PROVIDER: S-EPMC6263663 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ku Lawrence C LC Hornik Christoph P CP Beechinor Ryan J RJ Chamberlain James M JM Guptill Jeffrey T JT Harper Barrie B Capparelli Edmund V EV Martz Karen K Anand Ravinder R Cohen-Wolkowiez Michael M Gonzalez Daniel D

CPT: pharmacometrics & systems pharmacology 20180928 11

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 diazepa ...[more]

PMID: 30267478

Similar Datasets

Project description:Status epilepticus (SE) is a medical emergency associated with acute severe systemic damage and high mortality. Moreover, symptomatic SE is one of the highest risk factors for epileptogenesis. While the antiepileptic drugs (AEDs) are chosen in favor of acute control of SE, the potential short-term and long-term effects of such AEDs have been ignored in clinics. In this study, we hypothesized that AEDs that are used to control acute SE might affect the feasibility for the chronic development of epileptogenesis after SE. Therefore, we sought to compare the epileptogenic effects of SE that are terminated by three AEDs, i.e., diazepam, midazolam, and pentobarbital, which are widely used as first-line anti-SE AEDs. For this purpose, we used a mouse model of SE induced by intraperitoneal (i.p.) injection of lithium chloride (LiCl)-pilocarpine. The pilocarpine-induced SE was terminated with diazepam, midazolam, or pentobarbital. Then we compared short-term and long-term effects of SE with different AED treatments by examining SE-associated mortality and behavioral spontaneous recurrent seizures (SRSs) and by using magnetic resonance imaging (MRI) and immunohistochemistry to evaluate pathological and cellular alterations of mice in the different treatment groups. We found that i.p. injections of diazepam (5 mg/kg), midazolam (10 mg/kg), and pentobarbital (37.5 mg/kg) were able to terminate acute pilocarpine-SE effectively, while pentobarbital treatment showed less neuroprotective action against lethality in the short phase following SE. Long-term evaluation following SE revealed that SE treated with midazolam had resulted in relatively less behavioral SRS, less hippocampal atrophy, and milder neuronal loss and gliosis. Our data revealed an obvious advantage of midazolam vs. diazepam or pentobarbital in protecting the brain from epileptogenesis. Therefore, if midazolam provides as strong action to quench SE as other AEDs in clinics, midazolam should be the first choice of anti-SE AEDs as it provides additional benefits against epileptogenesis.

Project description:IntroductionConstant rate infusion (CRI) of benzodiazepines or propofol (PPF) is a therapeutic option for cluster seizures (CS) and status epilepticus (SE) in canine patients non-responding to first-line benzodiazepines or non-anesthetics. However, specific indications for optimal duration of CRI are lacking. The aim of this study was to determine the effect of duration of anesthetic CRI on outcome and length of hospital stay in dogs with refractory seizure activity of different etiology.Study designOpen-label non-randomized clinical trial.Materials and methodsSeventy-three client-owned dogs were enrolled. Two groups [experimental (EXP) vs. control (CTRL)] were compared. The EXP group received diazepam (DZP) or PPF CRI for 12 h (±1 h) and the CTRL group received DZP or PPF CRI for 24 h (±1 h) in addition to a standardized emergency treatment protocol identical for both study groups. The historical control group was made up of a population of dogs already reported in a previously published paper by the same authors. Favorable outcome was defined as seizure cessation after CRI, no seizure recurrence, and clinical recovery. Poor outcome was defined as seizure recurrence, death in hospital or no return to acceptable clinical baseline. Univariate statistical analysis was performed.ResultsThe study sample was 73 dogs: 45 (62%) received DZP CRI and 28 (38%) received PPF CRI. The EXP group was 39 dogs (25 DZP CRI and 14 PPF CRI) and the CTRL group 34 dogs (20 DZP CRI and 14 PPF CRI). We found no statistically significant difference in outcomes between the groups. The median length of stay was 56 h (IQR, 40-78) for the ALL EXP group and 58.5 h (IQR, 48-74.5) for the ALL CTRL group (p = 0.8).ConclusionEven though a shorter DZP or PPF CRI duration was not associated with a worse outcome, the study failed to identify a clear superiority of shorter CRI duration on outcome or length of hospital stay in dogs with refractory seizure activity of different etiology.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets