Study Finds Deutetrabenazine Metabolites Bioavailability Dose-Proportional
VANCOUVER, BC—The investigational vesicular monoamine transporter 2 (VMAT2) inhibitor deutetrabenazine (SD-809) for treating hyperkinetic movement disorder can be administered “without regard to the type of meal consumed,” according to authors of a small bioavailability study presented at the 68th Annual AAN Meeting.
“Following single-dose administration of deutetrabenazine (6mg, 12mg, 18mg, and 24mg), the active metabolites demonstrated dose proportional pharmacokinetics under fed conditions,” David Stamler, MD, of Teva Pharmaceuticals in La Jolla, CA, and coauthors reported in a poster presentation.
Deutetrabenazine is an investigational candidate treatment for hyperkinetic movement disorders, structurally related to tetrabenazine, which is approved for chorea management in patients with Huntington's Disease. Methoxy groups in tetrabenazine are replaced by trideuteronmethyoxy groups in deutetrabenazine, creating “important metabolic advantages” (including reduced variation in plasma concentrations) without changing target pharmacology, the coauthors wrote.
“Previous studies have shown that the active metabolites of deutetrabenazine, total (α + β)-dihydrodeutetrabenazine [HTBZ]) have a half-life of approximately 9 hours, thereby reducing the need for frequent dosing and reducing adverse events through to result from the peak concentrations associated with tetrabenazine,” the coauthors wrote.
The authors evaluated the relative bioavailability, dose proportionality, and safety of deutetrabenazine among patients who have been fed, at single doses of 6, 12, 18 and 24mg, in a randomized, open-label, 5-way crossover study of single deutetrabenazine dosing in healthy study participants. For all but one of the study arms, deutetrabenazine single-dose tablet was administered orally following a standard meal. A fifth study arm duplicated the 18mg deutetrabenazine dosing arm, but following a high-fat meal rather than a standard meal.
Plasma samples were collected, adverse events were monitored, and clinical laboratory, physical exam, ECG, and psychometric data were collected. Blood samples were collected pre-dose and at multiple time-points over 72 hours following dosing during each treatment period for determination of plasma concentrations of deutetrabenazine, α -HTBZ, and β-HTBZ, the authors noted. Pharmacokinetic endpoints (Cmax, AUC0-t, AUCinf, and t1/2) were then calculated.
A total of 32 patients were enrolled, of which 28 completed the study. Average participant age was 34 years and 53% were women; 94% of participants were white and the remaining 6% were African American.
“Study treatments were generally well tolerated,” the authors wrote. “A total of ten (31%) subjects reported adverse events, all of which were mild to moderate in severity. No serious AEs were reported and there was no evidence for a dose-response on the incidence of AEs. No safety concerns were observed regarding clinical labs, physical exams, ECG, and psychometric assessments.”
The average plasma concentrations of total (α + β)-HTBZ “appeared to increase in a dose-dependent matter with increasing dose of deutetrabenazine (6, 12, 18, and 24 mg administered with a standard meal),” they reported. “There was no effect of meal type on exposure, as indicated by the similar plasma-concentration profiles of the total (α + β)-HTBZ for deutetrabenazine 18mg administered with a standard or a high-fat meal.”
AUCinf was dose-dependent. “Based on an assessment of total (α + β)-HTBZ, deutetrabenazine doses 6mg to 24mg met criteria for bioequivalence,” they reported. “The relative bioavailability of HTBZ metabolites of deutetrabenazine 18mg with high fat meal compared with administration with a standard meal satisfied the criteria for equivalence,” they added.