Associate Director Pharmacometrics Teva Branded Pharmaceutical Products R&D LLC, West Chester, PA, United States, United States
Disclosure(s):
Dongwoo Kang: No financial relationships to disclose
Objectives: Deutetrabenazine is a vesicular monoamine transporter type 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia and chorea associated with Huntington disease [1]. Clinical studies have demonstrated the efficacy and safety of deutetrabenazine and characterized the pharmacokinetics (PK) [1,2]. This recent PK study, TV50717-PK-10198, was conducted in Asian individuals. The objective of this analysis was to further investigate the effect of deutetrabenazine exposure on Asian individuals using a combined PK dataset of existing data and TV50717-PK-10198 data.
Methods: PK models of deutetrabenazine and active metabolites were fitted to the combined dataset, including the data from TV50717-PK-10198 after administration of a single, 12-mg deutetrabenazine dose to Asian individuals. The other PK data of deutetrabenazine consist of mostly Western individuals. PK models of deutetrabenazine (parent) and active metabolites α-dihydrotetrabenazine (HTBZ) and β-HTBZ retained previously identified significant covariates; the effect on Asian individuals was then assessed along with other covariates. Stochastic approximation expectation maximization (SAEM) estimation as implemented in NONMEM v.7.4.0 was used to estimate values of system parameters and variability. Number of iterations for SAEM was adjusted as needed to achieve good convergence. Visual predictive checks were used to ensure a good fit of the models. The final model was used to simulate PK exposure following single dose and multiple doses, and then to compare Asian with Western individuals.
Results: Data from 20 Asian individuals from China (65% male; mean±SD age, 28.2±5.08 years; mean body weight±SD 65.0±9.51 kg) in TV50717-PK-10198 were merged with existing PK data, resulting in a combined dataset of 968 individuals. The individuals in the TV50717-PK-10198 study were administered one 12-mg deutetrabenazine tablet in a fed state. Since the Asian individuals had relatively lower body weights than Western individuals and 55% were intermediate CYP2D6 metabolizers, PK exposures were adjusted considering these factors. The adjusted PK exposures from Asian individuals were similar to those from the Western individuals. With the correction of body weight for extensive metabolizers at a steady state, Asian individuals had only a 5.8% higher mean area under the plasma concentration time curve and only a 14.7% higher mean maximum concentration for total (α+β)-HTBZ compared with Western individuals.
Conclusions: The population PK models of deutetrabenazine were refined with recently obtained data from an Asian population. With adjustments for body weight and CYP2D6 genotype status, the PK exposures are similar between the Asian and Western individuals.
Citations: [1] Austedo. Prescribing information. Teva Pharmaceuticals; 2021. [2] Schneider F, et al. Clin Pharmacol Drug Dev. 2021;10:647–659.
