Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data

Abstract

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure-related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36-mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose-ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4-5.7 years) for the active S(+)-enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one-compartment model with zero-order absorption and first-order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36-mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms.

Fifteen years of real‐world data on the use of vigabatrin in individuals with infantile epileptic spasms syndrome

“…All individuals were given an initial dose of 100 mg/kg/day of VGB, according to pharmacological simulations recommending a minimum dose of 80 mg/kg/day. 30 In the revised protocol, we shortened the time to evaluate VGB to 7 days instead of 20-25 days. We eliminated the additional time to titrate till 150 mg/kg/day due to the low response benefit (increase of 5% of responders) and the increased risk of persisting spasms affecting cognitive outcome.…”

“…Nevertheless, we decided to modify our protocol to implement the combination of hydrocortisone and VGB earlier (Figure 5). All individuals were given an initial dose of 100 mg/kg/day of VGB, according to pharmacological simulations recommending a minimum dose of 80 mg/kg/day 30 . In the revised protocol, we shortened the time to evaluate VGB to 7 days instead of 20–25 days.…”

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

“…Furthermore, it will be of interest to determine the VGB content of aqueous and vitreous humor, and retina using our method, with the prediction that the S‐(+) isomer will significantly concentrate in retina. Until such time as the issue of ocular toxicity of VGB is clarified, or mechanisms defined, caregivers will need to continue to cautiously monitor risk‐benefit associations with this unique antiepileptic agent …”

“…Until such time as the issue of ocular toxicity of VGB is clarified, or mechanisms defined, caregivers will need to continue to cautiously monitor risk-benefit associations with this unique antiepileptic agent. 54…”

Fluorimetric determination of the enantiomers of vigabatrin, an antiepileptic drug, by reversed‐phase HPLC with a novel diastereomer derivatization reagent

“…Vigabatrin (VB, Figure 1), an antiepileptic agent, is prescribed for young children and infants with epilepsy and has been reported to be effective for the treatment of infantile spasms (Ounissi et al, 2019). Vigabatrin has been designed as an analogue of γ ‐aminobutyric acid (GABA).…”