{Reference Type}: Journal Article
{Title}: Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil.
{Author}: Chanteux H;MacPherson M;Kramer H;Otoul C;Okagaki T;Rospo C;De Bruyn S;Watling M;Bani M;Sciberras D;
{Journal}: Expert Opin Drug Metab Toxicol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 27
{Factor}: 4.936
{DOI}: 10.1080/17425255.2024.2373108
{Abstract}: <B>UNASSIGNED: </B>Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug-interaction (DDI) profile of padsevonil.<BR><B>UNASSIGNED: </B>An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided.<BR><B>UNASSIGNED: </B>In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed.<BR><B>UNASSIGNED: </B>The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing.<BR><B>UNASSIGNED: </B>https://www.clinicaltrials.gov/identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.