Thank you for contacting Neurocrine Biosciences with your unsolicited Medical Information request regarding the effects of INGREZZA (valbenazine) capsules on the pharmacokinetic (PK) profile of concomitant drugs.
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 valbenazine to affect the PK of concomitant medications was assessed through in vitro and clinical studies (Loewen 2017, enclosed):2
Results from in vitro studies:2
- Valbenazine and [+]-α-HTBZ were weak direct inhibitors of cytochrome P450 2D6 (CYP2D6), but half maximal inhibitory concentration (IC50) values greatly exceeded typical therapeutic exposures; all other CYP IC50 values were greater than 9600 ng/mL
- No time-dependent inhibition of CYP enzymes by valbenazine and [+]-α-HTBZ was observed
- Neither valbenazine nor [+]-α-HTBZ induced CYP enzyme activity
- Valbenazine was a weak inhibitor of P-glycoprotein (P-gp) transport (IC50: 9950 ng/mL); but no other clinically-relevant effects of valbenazine or [+]-α-HTBZ on drug transporter activity were observed
Results from clinical studies:2
- Coadministration of valbenazine with midazolam (sensitive CYP3A4 substrate) did not affect midazolam PK
- Coadministration of valbenazine with digoxin (sensitive P-gp substrate) resulted in increased digoxin maximum concentration (Cmax) and area under the curve (AUC), without impacting digoxin t1/2
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 Valbenazine to Elicit Drug Interactions. 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 Valbenazine to Elicit Drug Interactions. Poster at 57th Annual Meeting of the American Society of Clinical Pyschopharmacology; May 29 – June 2, 2017; Miami, FL.
MED-MI-TD-US-0068