What are the pharmacokinetics of Deutetrabenazine (Austedo)?

From the FDA Drug Label

After oral dosing, plasma concentrations of deutetrabenazine are low compared to that of the active deuterated metabolites because of the extensive hepatic metabolism of deutetrabenazine. AUSTEDO XR Systemic exposure (i.e., peak plasma concentrations [Cmax] and the area under the plasma concentration-time curve [AUC]) for deutetrabenazine and the active, deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ, increased proportionally to dose following single doses of AUSTEDO XR over the recommended clinical dosage range (6 mg to 48 mg) AUSTEDO Systemic exposure (Cmax and AUC) for the active metabolites increased proportionally to dose following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22. 5 mg twice daily). Absorption Following oral administration of deutetrabenazine, the extent of absorption is at least 80%. AUSTEDO XR Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ, and β-HTBZ are reached within approximately 3 hours, followed by sustained plateaus for several hours allowing for a 24-hour dosing interval AUSTEDO Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ and β-HTBZ are reached within 3 to 4 hours after dosing. Distribution The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively Elimination AUSTEDO XR and AUSTEDO are primarily renally eliminated in the form of metabolites. The half-life of the active deuterated α-HTBZ, β-HTBZ, and total (α+β)-HTBZ metabolites is approximately 12 hours, 7. 5 hours, and 9 to 11 hours, respectively.

The pharmacokinetics of deutetrabenazine can be described as follows:

• Absorption: The extent of absorption is at least 80% following oral administration.
• Distribution: The median volume of distribution (Vc/F) of the α-HTBZ and β-HTBZ metabolites is approximately 500 L and 730 L, respectively.
• Elimination: Deutetrabenazine is primarily renally eliminated in the form of metabolites, with a half-life of approximately 12 hours, 7.5 hours, and 9 to 11 hours for the active deuterated α-HTBZ, β-HTBZ, and total (α+β)-HTBZ metabolites, respectively.
• Metabolism: Deutetrabenazine undergoes extensive hepatic metabolism to form active deuterated metabolites, including α-HTBZ and β-HTBZ.
• Systemic Exposure: Systemic exposure (Cmax and AUC) for the active metabolites increases proportionally to dose following single or multiple doses of deutetrabenazine 1.

From the Research

Deutetrabenazine has a pharmacokinetic profile characterized by rapid absorption, extensive first-pass metabolism, and a half-life of approximately 9-10 hours for its active metabolites, allowing for twice-daily dosing. The medication is a vesicular monoamine transporter 2 (VMAT2) inhibitor with distinct pharmacokinetic properties. After oral administration, deutetrabenazine is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations occurring within 3-4 hours 2. The medication undergoes extensive first-pass metabolism in the liver, where it is quickly converted to its active metabolites (α-HTBZ and β-HTBZ) by carbonyl reductase. These active metabolites are primarily responsible for the therapeutic effects. Food significantly increases deutetrabenazine bioavailability, with high-fat meals increasing exposure by approximately 50%, which is why it should be taken with food. The active metabolites are highly protein-bound (approximately 60-68%) and have a half-life of about 9-10 hours, allowing for twice-daily dosing. Elimination occurs primarily through hepatic metabolism followed by renal excretion of the metabolites. The deuterium substitution in deutetrabenazine (compared to tetrabenazine) slows down metabolism, providing more consistent blood levels and potentially fewer peak-dose side effects 2. This pharmacokinetic profile explains why deutetrabenazine is typically started at 6 mg once daily and gradually titrated to an effective dose, usually 6-24 mg twice daily, with doses separated by at least 6 hours.

Some key points to consider when prescribing deutetrabenazine include:

• The medication should be taken with food to increase bioavailability
• The active metabolites have a half-life of approximately 9-10 hours, allowing for twice-daily dosing
• The deuterium substitution slows down metabolism, providing more consistent blood levels and potentially fewer peak-dose side effects
• Deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 extensive metabolizers or poor metabolizers 3.

Overall, deutetrabenazine has a favorable pharmacokinetic profile that supports its use in the treatment of chorea associated with Huntington's disease and tardive dyskinesia.