Population Pharmacokinetic and Exposure‐Efficacy Analyses of Valbenazine in Patients with Huntington's Disease: Supporting Dose Selection for Chorea Management

Valbenazine improved chorea in individuals with Huntington's disease compared to placebo in a phase 3, placebo-controlled study (KINECT-HD). Population pharmacokinetics (PK) and exposure-response (E-R) analyses focused on understanding the PK characteristics of valbenazine and its active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ), and their correlation with clinical efficacy measured by the total maximal chorea (TMC) score. Consistent with previous analyses, a two-compartmental population PK model adequately described valbenazine and [+]-α-HTBZ plasma disposition, generating reliable individual-predicted exposure levels for sequential E-R analysis. The distributions of individual-predicted steady-state exposures of valbenazine and [+]-α-HTBZ were found to largely overlap between patients with tardive dyskinesia and those with Huntington's disease (HD) chorea. The relationship between the change from baseline in TMC score and [+]-α-HTBZ systemic exposure were effectively characterized by a nonlinear E_max model, with negligible impact from selected covariates. The predicted E-R curve closely aligns with the observed data, exhibiting a negative slope that indicates an increasing clinical response with escalating doses of 40, 60, and 80 mg/day. Predicted efficacy appears to reach a plateau at 80 mg once daily (QD), suggesting minimal additional benefit beyond this dosage. Together, results from the population PK model and E-R analyses reinforce the evidence base for valbenazine efficacy in reducing chorea severity, as demonstrated by the notable decrease in TMC scores compared to baseline. They also endorse the selection of dosing regimens ranging from 40 to 80 mg QD for the treatment of chorea in patients with HD.