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OBJECTIVE:

The purpose of this study was to characterize the drug-drug interactions involving clobazam and two antiseizure drugs, cannabidiol and stiripentol, for therapy of refractory seizures by way of the use of pharmacokinetic modeling.

Techniques:

A population pharmacokinetic/pharmacodynamic model was created to characterize the combined impact of clobazam and its active metabolite, N-desmethylclobazam (i.e., N-clobazam), on seizure protection in individuals with Lennox-Gastaut syndrome making use of information from the phase three Include trial. Drug-drug interactions involving clobazam and cannabidiol have been examined by comparing model-generated information to information from a study of 13 individuals taking concomitant clobazam and cannabidiol. Modeling information have been also descriptively compared with research of individuals administered each clobazam and stiripentol. Sedation-connected adverse events from Include have been analyzed to figure out the exposure-somnolence connection of clobazam.

Outcomes:

Exposure-efficacy evaluation from the pharmacokinetic/pharmacodynamic model making use of Include information indicated that clobazam (half-maximal productive concentration [EC50], 303 ng/mL) was three instances extra potent than N-clobazam (EC50, 899 ng/mL). Immediately after administration of clobazam, when each clobazam and N-clobazam concentrations have been every single 1 to two instances the EC50 worth (clobazam dose, 20 mg), 70.%-74.9% seizure protection was predicted when concentrations have been >2 instances the EC50 worth (clobazam dose, 40 mg), 74.%-96.9% seizure protection was predicted. Generalized additive model analyses demonstrated decreased seizure probability with larger plasma concentration of clobazam. Coadministration of stiripentol and clobazam resulted in improved respective median plasma concentrations of clobazam and N-clobazam (1.1-1.two instances and five.two-eight.two instances) compared with administration of placebo and clobazam. Probability of somnolence considerably improved with age and larger N-clobazam plasma concentration.

SIGNIFICANCE:

Awareness of drug-drug interactions involving clobazam and cannabidiol is necessary when adding cannabidiol or stiripentol to a regimen of clobazam or vice versa. Primarily based upon our population pharmacokinetic/pharmacodynamic model, we predict that an boost in N-clobazam levels, which patient information show may well improve efficacy and/or make adverse events such as somnolence extra most likely.

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