Thank you for contacting Neurocrine Biosciences with your unsolicited Medical Information request regarding the effects of concomitant medications on pharmacokinetics (PK) of INGREZZA (valbenazine) capsules.
INGREZZA is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia.1
Valbenazine is converted to an active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ; also referred to as (2R,3R,11bR)-dihydrotetrabenazine or O-desvalylvalbenazine), through the loss of L-valine by hydrolysis. The potential for concomitant medications to affect valbenazine and [+]-α-HTBZ pK was assessed through in vitro and clinical studies (Loewen 2017, enclosed):2
Results from in vitro studies:2
- Valbenazine was primarily metabolized to [+]-α-HTBZ by non-cytochrome P450 (CYP)-mediated hydrolysis and to oxidative metabolites by CYP3A4
- [+]-α-HTBZ was primarily metabolized by CYP2D6 and CYP3A4
- Valbenazine and [+]-α-HTBZ were highly membrane permeable
- Valbenazine and [+]-α-HTBZ were not P-gp substrates
Results from clinical studies:2
- Coadministration of valbenazine with ketoconazole, a strong CYP3A4 inhibitor, resulted in increased peak (Cmax) and overall (AUC) exposure to valbenazine and [+]-α-HTBZ
- Coadministration of valbenazine with rifampin, a potent CYP3A4 inducer, resulted in decreased peak and overall exposure to valbenazine and [+]-α-HTBZ
- Mean (±SD) dose-normalized valbenazine concentrations were similar (P=0.249) with (3.375±2.037 ng/mL/mg) or without (3.683±2.360 ng/mL/mg) concomitant CYP2D6 inhibitors
- Mean dose-normalized [+]-α-HTBZ concentrations were also similar (P=0.571) with (0.534±0.321 ng/mL/mg) or without (0.513±0.326 ng/mL/mg) concomitant CYP2D6 inhibitors
This letter and the enclosed material are provided in response to your unsolicited medical information inquiry. Please feel free to contact Neurocrine Medical Information at (877) 641-3461 or medinfo@neurocrine.com if you would like to request additional information.
References:
- INGREZZA [package insert]. Neurocrine Biosciences, Inc., San Diego, CA; 2017.
- Loewen G. et al. Evaluation of Potential for Concomitant Medications to Affect Valbenazine Pharmacokinetics. Poster at 57th Annual Meeting of the American Society of Clinical Pyschopharmacology; May 29 – June 2, 2017; Miami, FL.
Enclosures:
- INGREZZA [package insert]. Neurocrine Biosciences, Inc., San Diego, CA; 2017.
- Important Safety Information. Neurocrine Biosciences, Inc., San Diego, CA; 2017.
- Loewen G. et al. Evaluation of Potential for Concomitant Medications to Affect Valbenazine Pharmacokinetics. Poster at 57th Annual Meeting of the American Society of Clinical Pyschopharmacology; May 29 – June 2, 2017; Miami, FL.
MED-MI-TD-US-0069