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Abstract Details

Effect of Paroxetine on the Pharmacokinetics of Valbenazine and its Active Metabolite
Movement Disorders
P12 - Poster Session 12 (12:00 PM-1:00 PM)
3-017
To evaluate the effect of paroxetine on the pharmacokinetics of valbenazine and its active dihydrotetrabenazine (HTBZ) metabolite, [+]-α-HTBZ.

Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat tardive dyskinesia (TD) in adults. It is slowly metabolized to its active metabolite, [+]-α-HTBZ; no other HTBZ isomers are formed from valbenazine. This active [+]-α-HTBZ metabolite is subsequently metabolized, in part, by cytochrome P450 (CYP) 2D6. Patients with TD often receive multiple concomitant medications, some of which inhibit CYP2D6.
In this open-label, single-sequence study, 24 healthy subjects (excluding poor CYP2D6 metabolizers) received a single valbenazine 40 mg dose on Days 1 (Reference [R]) and 17 (Test [T]) after an overnight fast. Subjects received paroxetine 20 mg/day on Days 8-22. Blood samples to determine valbenazine and [+]-α-HTBZ plasma concentrations were obtained prior to and out to 144 hours following each valbenazine dose. Pharmacokinetic parameters, including peak plasma concentration (Cmax) and overall systemic exposure (AUClast and AUCinf), were determined using standard noncompartmental methods. Statistical analyses were conducted by determining the point estimate and two-sided 90% confidence interval (CI) for Test to Reference (T/R) differences of log-normalized pharmacokinetic parameters.

Mean plasma valbenazine concentration-time profiles were similar with and without paroxetine administration, while mean plasma [+]-α-HTBZ concentrations were higher when valbenazine was coadministered with paroxetine. T/R ratios of Cmax, AUClast and AUCinf were 76.0% (90% CI: 62.2-92.8%), 90.7% (90% CI: 76.1-108.1%), and 91.1% (90% CI: 77.1-107.8%), respectively, for valbenazine and 141.8% (90% CI: 117.7-170.8%), 189.6% (90% CI: 156.8-229.2%), and 190.2% (90% CI: 157.6-229.5%), respectively, for [+]-α-HTBZ. 

Coadministration of valbenazine with paroxetine, a potent CYP2D6 inhibitor, resulted in a 90% increase in exposure to the active metabolite [+]-α-HTBZ, but not valbenazine itself. In patients receiving a strong CYP2D6 inhibitor such as paroxetine, valbenazine dose reduction should be considered based on tolerability.
Authors/Disclosures

PRESENTER 		No disclosure on file
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No disclosure on file
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Grace L. Liang, MD Dr. Liang has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Liang has stock in Neurocrine Biosciences.