Population Pharmacokinetic and Exposure-Response Analyses of Valbenazine in Patients with Huntington’s Disease Chorea
Authors: Nguyen Hoa , Kuan H. Steve , Crass Ryan , Chapel Sunny , Thai-Cuarto Dao , Loewen Gordon , Brar Satjit 
Published: February 2025

Objectives: The analyses aimed to characterize the population pharmacokinetics (PK) of valbenazine and its primary active metabolite, [+]-α-dihydrotetrabenazine ([+]-α-HTBZ) and assess their relationship with clinical efficacy measured by the Total Maximal Chorea (TMC) score of the Unified Huntington’s Disease Rating Scale in patients with Huntington’s disease (HD) associated chorea. We also explored their impact on the most commonly reported treatment emergent adverse event (TEAE), somnolence, using a composite of somnolence-related AEs. Overall, the study sought to provide supportive evidence of valbenazine’s effectiveness and the proposed dosing regimen in treating HD-associated chorea.Methods: PK data from six phase 1 studies in healthy adults along with two phase 3 studies in patients with tardive dyskinesia (KINECT® 3, NCT02274558)1 and with HD-associated chorea (KINECT®-HD, NCT04102579)2, were combined to develop a joint parent-metabolite PK model for valbenazine and [+]-α-HTBZ. Individual subject empirical Bayes estimates of PK parameters were generated and merged with efficacy and safety endpoints from a pivotal Phase 3 HD study. Various longitudinal models were explored to describe changes in TMC score as a function of metabolite exposure, and the effects of intrinsic and extrinsic patient factors on efficacy were assessed. Furthermore, logistic-regression analyses were conducted to investigate somnolence-related events in relation to [+]-α-HTBZ and valbenazine exposure.Results: The systemic disposition of both valbenazine and [+]-α-HTBZ was adequately described by two-compartmental linear models. CYP2D6 metabolizer status emerged as the key intrinsic factor influencing [+]-α-HTBZ exposure. The nonlinear exposure-response (E-R) model effectively characterized the relationship between the change from baseline in TMC score and [+]-α-HTBZ systemic exposure, with minimal impact from selected covariates. The predicted E-R curve aligns with observed data, showing a negative slope, indicating increasing clinical response with escalating doses from 40 to 60 to 80 mg/day. Predicted response reaches a plateau at 80 mg once daily (QD), suggesting minimal additional benefit beyond this dosage. Additionally, exposure-safety modeling results reveal no significant association between valbenazine exposure and somnolence-related events, with a negligible relationship between [+]-α-HTBZ exposure and AE incidence.Conclusions. The population PK model successfully describes valbenazine and [+]-α-HTBZ disposition, generating reliable individual exposure levels for sequential E-R analyses. These E-R findings 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 support the favorable risk-benefit profile of valbenazine and endorse the selection of dosing regimens ranging from 40 to 80 mg QD for the treatment of chorea in patients with HD.Citations: [1] Hauser RA, Factor SA, Marder SR, et al. Am J Psychiatry. 2017;174:476-84.[2] Stimming EF, Claassen DO, Kayson E, et al. The Lancet Neurology. 2023 Jun 1;22(6):494-504.