Evaluating the efficacy of prototype antiseizure drugs using a preclinical pharmacokinetic approach

Abstract

ObjectivePharmacokinetics (PK) of a drug drive its exposure, efficacy, and tolerability. A thorough preclinical PK assessment of antiseizure medications (ASMs) is therefore essential to evaluate the clinical potential. We tested protection against evoked seizures of prototype ASMs in conjunction with analysis of plasma and brain PK as a proof-of-principle study to enhance our understanding of drug efficacy and duration of action using rodent seizure models. MethodsIn vivo seizure protection assays were performed in adult male CF-1 mice and Sprague-Dawley rats. Clobazam (CLB), N-desmethylclobzam (NCLB), carbamazepine (CBZ), carbamazepine-10,11-epoxide (CBZE), valproic acid (VPA), and levetiracetam (LEV) concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry. Mean concentrations of each analyte were calculated and used to determine PK parameters via non-compartmental analysis in Phoenix WinNonLin. ResultsNCLB concentrations were approximately 10-fold greater than CLB in mice. The antiseizure profile of CLB was partially sustained by NCLB in mice. CLB concentrations were lower in rats than in mice. CBZE plasma exposures were approximately 70% of CBZ in both mice and rats, likely contributing to the antiseizure effect of CBZ. VPA showed a relatively short half-life in both mice and rats, which correlated with a sharp decline in efficacy. LEV had a prolonged brain and plasma half-life, associated with a prolonged duration of action in mice. SignificanceThe study demonstrates the utility of PK analyses for understanding the seizure protection time-course in mice and rats. The data indicate that distinct PK profiles of ASMs between mice and rats likely drive differences in drug efficacy between rodent models. Key PointsO_LIThere exist potential contributions of active metabolites to the efficacy of some ASMs. C_LIO_LIThe utility of preclinical PK assessment of ASM is critical to guide our insight into a drug efficacy profile and provide a framework for subchronic dosing strategies. C_LIO_LISpecies-specific variations in PK profiles of ASMs in rodent models of epilepsy may underpin the differences in antiseizure effect in these models. C_LIO_LIPre-clinical drug screening of ASMs should include a (sub)chronic dosing paradigm to better mimic the dosing regimen in the clinic. C_LI