Summary: Purpose: Talampanel (LY300164), a potent and selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-receptor antagonist, is a potential new antiepileptic drug (AED). This study examines the single- and multiple-dose pharmacokinetics, safety, and tolerability of talampanel in patients with intractable epilepsy and assesses the potential for pharmacokinetic interaction.
Methods: Eleven of 14 patients entered into the study completed. Fourteen patients were evaluated for safety, 13 patients were used in the single-dose, and 11 patients in the multiple-dose pharmacokinetic analysis. Each patient initially received a single 35-mg dose of talampanel followed by the measurement of pharmacokinetic profiles. A 21-day t.i.d. dosing regimen was then determined for each patient based on his or her initial pharmacokinetic profile. Adverse events were recorded by patients or their carers.
Results: After oral ingestion, talampanel was rapidly absorbed, with maximal plasma concentrations achieved within 1–3 h. Talampanel concentrations in patients taking enzyme-inducing AEDs were 50% lower than those seen in healthy volunteers. Mean talampanel t1/2 values were 3.0 h compared with 4.2 h in healthy volunteers. After multiple-dose and steady-state, talampanel t1/2 values were increased to 5.6 h Talampanel and valproic acid (VPA) appear to inhibit each other's metabolism mutually. Talampanel had no effect on plasma concentrations of other AEDs. Multiple-dose talampanel administration was associated with nonlinear pharmacokinetics. No serious adverse events were reported; the most frequently reported being dizziness, ataxia, drowsiness, and headaches
Conclusions: Talampanel dosing strategies may be reliant on concomitant AED medication, as enzyme-inducing AEDs enhance, whereas VPA inhibits its metabolism. Talampanel was well tolerated, although adverse events occurred at lower doses compared with those in healthy subjects, probably because of the additive effect of concomitant AEDs.