Abstracts

Rationale: Brivaracetam (BRV), a selective high-affinity ligand for synaptic vesicle protein 2A, was recently approved in the EU, USA, and Canada as adjunctive therapy for focal (partial-onset) seizures in adults with epilepsy. Phenytoin (PHE), a widely used antiepileptic drug, has a variable/complex pharmacokinetic (PK) profile and narrow therapeutic index. We conducted a clinical interaction study in patients with epilepsy, in vitro investigations, and physiologically based pharmacokinetic (PBPK) modeling to predict the effect of BRV on PHE exposure. Methods: An open-label study evaluated the effect of steady-state BRV (200 mg/day for 3 days, followed by 400 mg/day maintenance dose [twice the maximum approved dose] for 21 days) on the steady-state PK of PHE (200?'700 mg/day, in one or two daily doses, stable for at least 3 months) in 19 adult patients (18?"65 years) with epilepsy (N01172/NCT00426673). In vitro assays investigated the inhibition by BRV of human liver microsomal (HLM) CYP isoforms; and the effect of BRV and its metabolites on the 4-hydroxylation of PHE by human recombinant CYP2C9 and 2C19. Finally, PBPK modeling (Simcyp?(R) Simulator v14) explored the PK interaction of BRV on PHE. A PBPK model for BRV was developed using data from a BRV clinical study (EP0007/NCT01796899). The PBPK model was validated for PHE (default parameters) from published in vitro and clinical CYP2C19-related drug?'drug interaction data. The fraction of PHE transformed by CYP2C19 was set to 10%, based on literature data. BRV's effect on omeprazole, a drug primarily eliminated via CYP2C19, was also modeled. Results: In the PK study, BRV increased PHE maximum plasma concentration and AUCT by ~20% (Table). PHE exposure was highly variable in general. BRV was generally well tolerated. In HLM, BRV competitively inhibited CYP2C19 with a Ki inhibition constant of 314 M, but had no effect on CYP1A2, 2A6, 2C8, 2C9, 2D6, 3A4 or P-glycoproteins at concentrations up to 650 M. In vitro, PHE was metabolized by CYP2C9 (~97%) and, to a lesser extent, by CYP2C19 (~3%). Neither BRV (up to 200 M) nor its metabolites inhibited CYP2C9-mediated 4-hydroxylation of PHE. BRV inhibited CYP2C19-mediated 4-hydroxylation of PHE with a median inhibition concentration (IC50) of 200 M; BRV metabolites had no effect. BRV plasma concentrations were adequately predicted by the PBPK model. Co-administration of BRV up to 400 mg/day was predicted to have a negligible effect on PHE exposure (~2% increase; Figure). BRV was predicted to have no effect on omeprazole exposure, providing further support for the lack of effect of BRV on CYP2C19-mediated metabolism. Conclusions: A PK interaction study in patients with epilepsy suggested that a supratherapeutic dose of BRV may produce a modest increase in PHE exposure. In vitro studies confirmed that BRV could weakly inhibit PHE metabolism (through CYP2C19 inhibition). However, a validated PBPK model predicted that recommended doses of BRV (50?"200 mg/day) should not affect exposure to PHE or to other CYP2C19 clinical substrates. Figure. Simulated steady-state plasma profile of phenytoin (800 mg/day in two divided doses for 34 days) without (blue line) and with (orange line) steady-state dosing of brivaracetam (200 mg/day in two divided doses for 3 days and then 400 mg/day in two divided doses for 21 days). The line represents the overall mean of a virtual population (n=190). Funding: UCB Pharma funded