From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications

Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug of the chiral compound licarbazepine. Of the 17 chiral ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol and vigabatrin) are marketed as racemates, and the remainder are licensed as enantiomerically pure medicines. Of note, all chiral ASMs introduced prior to 1990 were marketed as racemates. Stiripentol, fenfluramine and vigabatrin are the only racemic ASMs approved by the FDA >10 years after the release of regulatory guidelines on the development of chiral medicines. Despite the fact that pharmacokinetic and pharmacodynamic differences between enantiomers have been recognized for decades, the importance of chirality in understanding the biological actions of ASMs is not widely appreciated, and many recent publications on racemic ASMs refer to these medications as if they were a single molecular entity. In the present article, we provide a critical review of chiral ASMs developed between the 1920s, when mephobarbital was introduced, and 2022, when the last chiral ASM (ganaxolone) was approved. We summarize available data on stereoselective differences in pharmacokinetics and pharmacodynamics of ASMs marketed as racemates. We also discuss regulatory aspects related to the introduction of racemic medicines within the current regulatory scenario in Europe and the U.S., focusing on stiripentol, vigabatrin and fenfluramine as examples of different approaches. We identified a number of critical knowledge gaps that are relevant to the use of chiral drugs in epilepsy, including a remarkable lack of published information on the comparative pharmacokinetics, toxicity and antiseizure activity of the enantiomers of most racemic ASMs. The importance of chirality aspects in understanding the clinical actions of racemic ASMs is discussed, together with the rationale for the development of enantiomerically pure follow-up compounds with potentially improved efficacy, safety and commercial viability.