Antiepileptic drugs: evolution of our knowledge and changes in drug trials

Abstract

Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938–1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970–1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989–2019) was dominated by the introduction of second‐generation drugs, and further evolution in the design of monotherapy and adjunctive‐therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second‐generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.

Development of Antiepileptic Drugs throughout History: From Serendipity to Artificial Intelligence

“…Some of them were approved by some countries with results obtained from uncontrolled observational clinical studies. However, by the 1970s, controlled studies began to be designed, which expanded approvals by the FDA to include drugs such as carbamazepine or valproic acid [ 69 ].…”

“…This has provided a better understanding of pharmacokinetics, individualization of doses, therapeutic drug monitoring, drug interactions, clinical response, spectrum of activity, and adverse effects of AEDs. Furthermore, results from many of these studies led to the understanding that polypharmacy is associated with toxicity without improving seizure control, and that monotherapy can achieve seizure control with drug-level monitoring [ 69 ].…”

“…For example, a double-blind randomized trial by White et al [ 71 ] comparing phenobarbital, primidone, phenytoin, and carbamazepine sought to identify the antiepileptic medication with the best efficacy and found that phenytoin had the best antiseizure activity. In addition, the authors proposed the maximum dose for each one of the medications in the trial to provide the patient with the best outcome measured in seizure activity [ 69 ]. The definition of second-generation AEDs varies depending on the exact year they were introduced; however, molecules such as felbamate, one of the first second-generation AEDs marketed in the United States, was introduced in the year 1993, with many other second-generation AEDs emerging between the end of the 1980s and the early 1990s [ 72 ].…”

Imperatorin interacts additively with novel antiseizure medications in the mouse maximal electroshock-induced seizure model: an isobolographic transformation

“…The rationale for investigating in this study the influence of IMP on the anticonvulsant potencies of four novel ASMs in the mouse MES model was based primarily on two premises. Firstly, novel ASMs (including, LCM, OXC, PGB, and TPM) are safer, more efficient, and better tolerated by the patients than classic ASMs [ 17 , 18 ]. The studied novel ASMs (i.e., LCM, OXC, PGB, and TPM) are preferentially prescribed to patients, whose tonic–clonic seizures are not satisfactorily controlled with classic ASMs due to either intolerable high doses of ASMs used or adverse events that appear during the treatment with classic ASMs.…”

Phytocannabinoids Reduce Seizures in Larval Zebrafish and Affect Endocannabinoid Gene Expression

“…Animal models play a crucial role in epilepsy research, and some of the original ASMs were discovered after studies on animal models, as discussed by Perucca, 2019 [ 7 ]. The non-competitive GABA A receptor antagonist pentylenetetrazole (PTZ), for example, invokes concentration-dependent seizure-like behavior in rodents and zebrafish [ 8 , 9 , 10 , 11 ].…”