Pharmacokinetic profile of metaclazepam (Talis), a new 1.4-benzodiazepine. Influence of different dosage regimens on the pharmacokinetic profile of metaclazepam and its main metabolite under steady-state conditions.

The pharmacokinetic parameters of the new 1.4-benzodiazepine metaclazepam (Talis) were investigated. In particular, the question of whether the drug and/or its main metabolite accumulates in the body under steady-state conditions was studied. Two dosage regimens were compared by a randomized two-way crossover design: a once-a-day dosing (15 mg metaclazepam in the evening, = A) versus a twice-a-day dosing (5 mg in the morning plus 10 mg in the evening, = B) over ten days in twelve healthy male volunteers. Plasma levels of metaclazepam and its major biotransformation product, N-desmethylmetaclazepam, were determined. Comparing the treatments, significant differences were found for Cmax, but not for AUC-3 and Tmax. These results are also valid for the comparison of days 1 and 10 of each treatment. Higher Cmax values for dosage regimen A were found but Tmax and Cl/F remained stable in both treatments taking into account that 12 hours after the first medication, another dosing took place in treatment B. Eight hours after application, plasma levels were markedly low, Cmax values after single-dosing were nearly twice as high as after multiple dosing. Therefore based on these pharmacokinetic findings, a second dosing seems to be necessary; the clinical relevance needs further investigation. It has been reported, in fact, that it is in general very difficult to demonstrate a correlation between blood levels and therapeutic effects for 1.4-benzodiazepines (1,2).