Abstract
<jats:p>Drug-resistant epilepsy (DRE) remains a major therapeutic challenge despite the availability of numerous antiseizure medications (ASMs). Clinical observations suggest that, in some patients, the addition of low-dose clobazam to an established cenobamate regimen may be associated with improved seizure control. The biological basis of this observation, however, remains uncertain. This study aimed to develop a multiscale structural, pharmacokinetic/pharmacodynamic (PK/PD) and systems pharmacology framework to explore whether currently available pharmacological knowledge supports a plausible mechanistic explanation for this potential interaction. A systems pharmacology framework integrating qualitative structure–activity characterization, pharmacokinetic interaction analysis and pharmacodynamic network interpretation was developed. Molecular and pharmacological features relevant to GABAergic modulation, sodium-channel activity, SV2A interaction, blood–brain barrier penetration and metabolic behaviour were considered for cenobamate, clobazam, norclobazam, brivaracetam and lacosamide. The framework incorporated the established inhibition of CYP2C19 by cenobamate together with pharmacodynamic mechanisms that may influence neuronal excitation–inhibition balance. The objective was not to predict clinical efficacy quantitatively but to evaluate whether the available pharmacological evidence supports a biologically plausible mechanistic hypothesis. The integrated framework identified complementary pharmacological properties between cenobamate and clobazam that could plausibly contribute to antiseizure activity. The established pharmacokinetic interaction whereby cenobamate inhibits CYP2C19 provides a plausible explanation for increased norclobazam exposure, while complementary pharmacodynamic mechanisms may further influence inhibitory network activity. Brivaracetam and lacosamide, considered as stable background therapy, provide additional antiseizure mechanisms but are not considered the primary drivers of the proposed interaction. Overall, the framework supports the biological plausibility of a potential cenobamate–clobazam interaction without establishing causality. These findings provide a mechanistic framework consistent with clinical observations suggesting that low-dose clobazam may contribute to the antiseizure activity observed during cenobamate treatment in selected patients with drug-resistant epilepsy. The proposed framework should be regarded as hypothesis-generating and intended to support future experimental and clinical studies aimed at clarifying mechanism-based polytherapy.</jats:p>