Balancing Efficacy and Safety in Patients With Tardive Dyskinesia Treated With Deutetrabenazine by Investigating Exposure–Response Relationships

Background: Deutetrabenazine (DTBZ) is used for the treatment of tardive dyskinesia (TD) and chorea associated with Huntington disease. DTBZ dosing starts at 12 mg/d and is titrated up by 6 mg weekly, based on efficacy and tolerability, to a maximum of 48 mg/d. Due to individual variability in the pharmacokinetics of DTBZ, the dose needs to be titrated to an optimal dose for each individual while balancing efficacy and safety. To provide more information on individualized dosing, the relationship between increased DTBZ exposure and the probability of achieving treatment success or experiencing an adverse event (AE) was investigated.

Methods: Population pharmacokinetic models for DTBZ (parent) and its metabolites (α- and β-dihydrotetrabenazine [HTBZ]) were developed based on phase 1 studies in healthy volunteers and phase 3 studies in patients. Logistic regressions were performed to compare the associations of total exposure of (α+β)-HTBZ for subjects who had selected AEs and to determine the probability of achieving treatment success (defined as much/very much improved) based on Clinical Global Impression of Change and Patient Global Impression of Change scales.

Results: The probability of DTBZ efficacy was dose proportional to (α+β)-HTBZ exposure within the clinical dosing range (12–48 mg). However, regarding safety, no dose-proportional response was observed between (α+β)-HTBZ exposure and selected AEs (ie, akathisia, depression, diarrhea, insomnia, somnolence).

Conclusion: These exposure–response results suggest that DTBZ can be up-titrated to increase the likelihood of treatment benefit without increasing the risk of AEs.