Clinical drug investigation · 2026
Assessment of Dose Proportionality and the Effect of Food on a Once-Daily Extended-Release Tablet Formulation of Deutetrabenazine in Healthy Participants.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Sunzel Eva-Maria, Ghibellini Giulia, Gutierrez Maria, Ruffo Debra, Chavan Shailendra, Birajdar Nagnath G, Schneider Frank, Loupe Pippa, Gordon Mark Forrest, Rabinovich-Guilatt Laura
Аннотация
BACKGROUND AND OBJECTIVE: Deutetrabenazine is approved as a treatment in adults for tardive dyskinesia and chorea associated with Huntington's disease. A once-daily tablet (Austedo XR® Teva) was recently approved in addition to the twice-daily tablet (Austedo®), and studies were conducted to evaluate dosage strength proportionality and food effect of the once-daily formulation.
METHODS: In a randomized cross-over study of dosage strength proportionality, healthy participants (n = 116) received single doses of the once-daily deutetrabenazine formulation and a power model was fitted to describe the relationship between dose and pharmacokinetic parameters (maximum observed plasma drug concentration [Cmax], area under the plasma concentration-time curve from time 0 to 36 h [AUC0-36h], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC0-∞]). In the second cross-over study, a single 24-mg dose of the once-daily formulation was given in fasted and fed conditions to healthy participants (n = 84) and the effect of food was evaluated by constructing 90% confidence intervals of the geometric mean ratios for Cmax, AUC0-t, and AUC0-∞. RESULTS: Dosage strength proportionality for the once-daily formulation was demonstrated for the dosage strengths 6 mg, 12 mg, and 24 mg; and across the approved dose range up to 48 mg for the pharmacokinetic parameters of all analytes (deutetrabenazine, and metabolites; deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine), individually and as a sum). In the food effect study, the Cmax, AUC0-t, and AUC0-∞ geometric mean ratios for deutetrabenazine and deuterated metabolites all fell within the 90% confidence interval of 80-125.
CONCLUSIONS: The once-daily formulation of deutetrabenazine exhibited dosage strength proportional pharmacokinetics for doses up to 48 mg and there was no observed effect of food.
METHODS: In a randomized cross-over study of dosage strength proportionality, healthy participants (n = 116) received single doses of the once-daily deutetrabenazine formulation and a power model was fitted to describe the relationship between dose and pharmacokinetic parameters (maximum observed plasma drug concentration [Cmax], area under the plasma concentration-time curve from time 0 to 36 h [AUC0-36h], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC0-∞]). In the second cross-over study, a single 24-mg dose of the once-daily formulation was given in fasted and fed conditions to healthy participants (n = 84) and the effect of food was evaluated by constructing 90% confidence intervals of the geometric mean ratios for Cmax, AUC0-t, and AUC0-∞. RESULTS: Dosage strength proportionality for the once-daily formulation was demonstrated for the dosage strengths 6 mg, 12 mg, and 24 mg; and across the approved dose range up to 48 mg for the pharmacokinetic parameters of all analytes (deutetrabenazine, and metabolites; deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine), individually and as a sum). In the food effect study, the Cmax, AUC0-t, and AUC0-∞ geometric mean ratios for deutetrabenazine and deuterated metabolites all fell within the 90% confidence interval of 80-125.
CONCLUSIONS: The once-daily formulation of deutetrabenazine exhibited dosage strength proportional pharmacokinetics for doses up to 48 mg and there was no observed effect of food.