Pharmacokinetics, safety and tolerability of valbenazine in Korean CYP2D6 normal and intermediate metabolizers

Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for tardive dyskinesia treatment by the US Food and Drug Administration; its major active metabolite (NBI‐98782) is a 45‐fold more potent inhibitor of VMAT2 than the parent drug. This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability and the effect of cytochrome P450 2D6 (CYP2D6) genotypes to the PKs after the administration of valbenazine in Korean participants. A randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose study was conducted in healthy Korean male participants. The single‐dose study was conducted for both 40 and 80 mg valbenazine and the multiple dose study was conducted for 40 mg. After a 1‐week washout, the 40 mg dose group participants received valbenazine 40 mg or placebo once daily for 8 days. Serial blood samples were collected up to 96 h postdose for PK analysis. The CYP2D6 genotypes of the participants were retrospectively analyzed. A total of 50 participants were randomized, and 43 and 20 participants completed the single‐ and multiple‐dose phases of the study, respectively. After single doses, the PK characteristics of valbenazine and its metabolites were similar between the 40 and 80 mg dose groups. After multiple doses, the mean accumulation ratios of valbenazine and NBI‐98782 were ~1.6 and 2.4, respectively. Plasma concentrations of valbenazine and NBI‐98782 were similar between CYP2D6 normal and intermediate metabolizers. Valbenazine was well‐tolerated in healthy Koreans, and its PK characteristics were similar to results previously reported in Americans.