Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups

Abstract

Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia-ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM. Concentration-time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed-effect modeling. Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 μg/ml in Long Evans and 39.9 and 24.4 μg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 μg/ml in Long Evans and 66.5 and 40.6 μg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups. TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies.