Pharmacokinetic and Pharmacodynamic Evaluation of Intravenous Levetiracetam in Children With Epilepsy

Abstract

This study aimed to evaluate the safety and tolerability of intravenous (IV) levetiracetam (LEV) as a monotherapy in children aged 1 month-16 years and to explore the pharmacokinetics (PK) of IV LEV and the time to seizure after IV then oral administration of LEV in pediatric children with epilepsy. Children diagnosed with acute unprovoked seizures requiring in-hospital IV LEV administration were included. After administration, the clinical seizure outcomes, side effects, and the Korean-Child Behavior Checklist were monitored and the PK and repeated time to seizure were analyzed via modeling using NONMEM software. Overall, 37 children with epilepsy were enrolled and underwent a PK analysis (median age, 4.6 years; median weight, 18.0 kg). Nine children (24.3%) had seizure recurrence during the follow-up period (median, 3.8 months) and 5 children (13.5%) experienced LEV-associated adverse events such as irritability (n = 2; 5.4%) and somnolence (n = 3; 8.1%). The plasma LEV concentrations after IV LEV were best described by a one-compartment linear PK model. Only body weight was associated with both the clearance and volume of distribution of LEV. The Weibull distribution model described the time to seizure recurrence well; no statistically significant predictor for the time to seizure was identified. Therefore, IV LEV was a well-tolerated and effective alternative in children with acute unprovoked seizures, and models for the PK and time to repeated seizure recurrence after LEV were successfully developed. In particular, the current use of a weight-based IV LEV dosing regimen in pediatric children is practical.

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

“…Reports have suggested that miR‐135a‐5p confer neuronal protection in mice with Alzheimer's disease by regulating potassium channels. KCNQ3 is a gene encoding a potassium ion channel and is widely expressed in brain and sympathetic ganglia . Potassium channels are closely related to the electrical activity of central neurons, and their structural and functional abnormalities will alter neuronal excitability and cause seizures .…”

“…KCNQ3 is a gene encoding a potassium ion channel and is widely expressed in brain and sympathetic ganglia. 33 Potassium channels are closely related to the electrical activity of central neurons, and their structural and functional abnormalities will alter neuronal excitability and cause seizures. 34 During the current experiment, the online prediction software Targetscan was used to demonstrate that miR-135a-5p could bind to the 3 0 UTR of KCNQ3.…”

A Review of Population Pharmacokinetic Studies of Levetiracetam

“…Sneck et al [13] enrolled only healthy subjects, Pigeolet et al included both patients and healthy subjects [14], and the other studies were conducted in patients with epilepsy [15-26]. Eight of the fourteen studies enrolled paediatric patients [15, 17, 18, 20, 21, 24-26]; 2 studies were conducted in neonates [18, 21], 4 studies in children less than 18 years of age [15, 20, 25, 26], and 2 studies included both children and adults [17, 24]. Three study only enrolled adults [13, 14, 19], and the other three studies included elderly patients of over 70 years [16, 22, 23].…”

“…The LEV PK for oral formulations was described with a one-compartment model with first-order absorption and elimination, and for injections was described with a one- or two- compartment model with first order elimination. Two studies conducted in neonates [18, 21], three in children [20, 26], and five in adults were based on sparse sampling data from the routine clinical TDM settings [16, 17, 19, 22, 23], and other four studies included intensive sampling data [13-15, 25]. The number of participants in each study ranged from 7 to 524, with LEV observations per individual ranging from 1 to 10.…”

“…The characteristics of each study are summarised in Table 1. Sneck et al [13] enrolled only healthy subjects, Pigeolet et al included both patients and healthy subjects [14], and the other studies were conducted in patients with epilepsy [15][16][17][18][19][20][21][22][23][24][25][26]. Eight of the fourteen studies enrolled paediatric patients [15,17,18,20,21,[24][25][26]; 2 studies were conducted in neonates [18,21], 4 studies in children less than 18 years of age [15,20,25,26], and 2 studies included both children and adults [17,24].…”