Pharmacokinetics of Loading Dose Vigabatrin Administered via Enteral Tube in Participants With Post‐Anoxic Status Epilepticus

INTRODUCTION: Post-anoxic status epilepticus (PASE) is a frequent neurologic complication following hypoxic-ischemic brain injury in cardiac arrest survivors, for which no definitive treatment exists. Early γ-Aminobutyric Acid (GABA) augmentation using vigabatrin, a GABA-transaminase inhibitor, has been proposed; however, its pharmacokinetics (PK) in this critically ill population are unknown. In this ancillary study of VIGAB-STAT, an open-label feasibility trial of loading dose vigabatrin via enteral tube, we evaluated vigabatrin PK. MATERIALS AND METHODS: Comatose adults with electrographic status epilepticus following return of spontaneous circulation received a loading dose of vigabatrin determined by renal function (creatinine clearance (CrCl) ≥ 50 mL/min, 4500 mg; CrCl 30-50 mL/min, 2250 mg; CrCl < 30 mL/min, 1125 mg). Pharmacokinetic sampling occurred at 0 (pre-dose), 0.5, 1, 2, 3, 6, 12, 24, 48, 72, and 168-h post-dose, and plasma concentrations were quantified using liquid chromatography tandem mass spectrometry. PK parameters were estimated using non-compartmental analysis. RESULTS: Six participants contributed 56 plasma samples. The median (range) age was 62 years (22-68), weight 80.9 kg (57.6-139.9), and four (66.7%) participants were male. Loading doses were evenly distributed: 4500 mg (n = 2), 2250 mg (n = 2), and 1125 mg (n = 2). Time to maximum concentration, maximum concentration, area under the concentration time curve from 0 to 24 h, area under the concentration time curve from 0 to infinity and half-life median (range) values were 2 h (1-3), 38.1 mg/L (16.9-91.8), 431.2 mg*h/L (254.6-979.3), 679.3 mg*h/L (340.3-1156.8), and 16.2 h (9.4-23.9), respectively. CONCLUSIONS: This pioneer vigabatrin PK study in critically ill participants with PASE demonstrated absorption regardless of challenges such as enteral delivery type, co-administration of gastric pH modulators, vasopressors, and anesthetics. Notably, prolonged elimination half-lives and increased exposures were observed.