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Dose‐dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship
Author(s) -
KasteleijnNolst Trenité Dorotheé,
Brandt Christian,
Mayer Thomas,
Rosenow Felix,
Schmidt Bernd,
Steinhoff Bernhard J.,
Gardin Anne,
Imbert Georges,
Johns Donald,
Sagkriotis Alexandros,
Kucher Klaus
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13008
Subject(s) - medicine , tolerability , pharmacodynamics , ampa receptor , dosing , antagonist , pharmacokinetics , pharmacology , anesthesia , adverse effect , glutamate receptor , receptor
Summary Objective Examine the efficacy of a competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid ( AMPA )/kainate glutamate receptor antagonist, selurampanel ( BGG 492), in the human photostimulation model. Methods Patients with epilepsy and a generalized epileptiform electroencephalography response to intermittent photic stimulation (photoparoxysmal response or PPR ; diagnosed ≥6 months prior to initial study dosing) were enrolled in a phase II , multicenter, single‐blind, within‐subject, placebo‐controlled proof‐of‐concept (PoC) study. PPR was used as a biomarker to assess the efficacy and safety of BGG 492 in three cohorts (cohorts I– III received BGG 492 50, 100, and 15 mg, respectively). Primary endpoints were to evaluate the efficacy of single oral BGG 492 doses in abolishment of PPR or a relevant reduction of the standardized photoparoxysmal response ( SPR ), and to evaluate time of onset and duration of response. Secondary endpoints were to evaluate maximal SPR reduction, determine the pharmacokinetic profile of BGG 492, explore the pharmacokinetic/pharmacodynamic relationship, and evaluate the safety and tolerability of BGG 492. Results Ten patients were enrolled, with three participating twice, that is, in two cohorts (n = 13). Treatment with BGG 492 resulted in abolition of PPR in seven of 13 patients in a dose‐dependent manner: three, three, and one patient in cohorts I– III , respectively. All patients showed treatment‐related reductions of SPR range of at least three steps in at least one eye condition (eye closure, eyes closed, or eyes open). Generally, onset of the suppressive effect appeared to be within 1–2 h post‐ BGG 492 dose and continued in three patients at the 50‐ and 100‐mg doses for 29–33 h. Most common adverse events across the BGG 492‐treated groups were headache and nasopharyngitis (three patients each), followed by dizziness, fatigue, and diarrhea (two patients each). Significance The dose‐dependent positive effect of BGG 492 on the PPR and SPR in patients with photosensitive epilepsy in this proof‐of‐concept study supports further investigation of AMPA receptor antagonists in large‐scale phase III trials.