Pharmacokinetics and Safety of Vortioxetine in the Chinese Population

Jia Miao, Gang Wang, Jie Hou, Johan Areberg, Yan Zhao, Astrid-Maria Højer, Anders Ettrup, Jia Miao, Gang Wang, Jie Hou, Johan Areberg, Yan Zhao, Astrid-Maria Højer, Anders Ettrup

Abstract

Introduction: Major depressive disorder (MDD) is associated with a significant burden of disease in China. Awareness and better access to treatments could help alleviate the burden associated with MDD. Because variations have been observed in the pharmacokinetics (PK) of antidepressants across different races and ethnicities, evaluation of the clinical pharmacology of vortioxetine in diverse populations remains important to assess the potential need for dose adjustments.

Methods: Data were pooled from two phase I open-label PK studies in healthy Chinese subjects, and one phase III double-blind noninferiority study in Chinese patients with MDD to describe the PK and safety data for vortioxetine. Doses in these studies ranged from 10 mg (single dose) to 10 and 20 mg (multiple daily doses). A population PK analysis of vortioxetine in the Chinese population was conducted using nonlinear mixed-effect modeling.

Results: In total, 186 individuals were included in the PK analysis: 79 healthy Chinese subjects and 107 Chinese patients with MDD. No clinically significant differences in the PK of vortioxetine were observed between the Chinese population and the previous data in non-Chinese populations. Because of a generally lower weight in the Chinese population compared with the non-Chinese population, exposures were 19% and 18% higher in the Chinese population than in the non-Chinese population (for maximum observed plasma concentration and area under the plasma concentration-time curve, respectively), which is not considered clinically relevant. A high prevalence of pruritus was observed in one phase I PK study (56% overall); however, this was not reflected in the phase III study in Chinese patients with MDD (0.8%).

Conclusions: The PK parameters of vortioxetine in Chinese subjects were comparable to previous data in non-Chinese subjects. Overall, no new safety concerns were raised among the Chinese population. On the basis of this analysis, the tolerability profile of vortioxetine in Chinese healthy subjects and in patients with MDD is expected to be comparable to that in the non-Chinese population.

Funding: H. Lundbeck A/S, Valby, Denmark.

Trial registration: NCT01676571.

Keywords: Antidepressant; Chinese; Healthy subjects; Major depressive disorder; Pharmacokinetics; Vortioxetine.

Figures

Fig. 1
Fig. 1
Schematic of PK model for vortioxetine. ALAG lag time, CL/F oral clearance, ka absorption rate constant, PK pharmacokinetics, Q/F intercompartmental clearance, V2/F volume of distribution of central compartment, V3/F volume of distribution of peripheral compartment
Fig. 2
Fig. 2
Observed plasma concentration (dose-normalized to 10 mg) at steady state together with model-predicted median and 95% CI. CI confidence interval

References

    1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1211–1259. doi: 10.1016/s0140-6736(17)32154-2.
    1. Gu L, Xie J, Long J, et al. Epidemiology of major depressive disorder in mainland China: a systematic review. PLoS One. 2013;8:e65356. doi: 10.1371/journal.pone.0065356.
    1. Hou Z, Jiang W, Yin Y, Zhang Z, Yuan Y. The current situation on major depressive disorder in China: research on mechanisms and clinical practice. Neurosci Bull. 2016;32:389–397. doi: 10.1007/s12264-016-0037-6.
    1. Gupta S, Goren A, Dong P, Liu D. Prevalence, awareness, and burden of major depressive disorder in urban China. Expert Rev Pharmacoecon Outcomes Res. 2016;16:393–407. doi: 10.1586/14737167.2016.1102062.
    1. TRINTELLIX [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2018.
    1. BRINTELLIX [summary of product characteristics]. Valby, Denmark: H. Lundbeck A/S; 2019.
    1. Bang-Andersen B, Ruhland T, Jorgensen M, et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011;54:3206–3221. doi: 10.1021/jm101459g.
    1. Chen G, Hojer AM, Areberg J, Nomikos G. Vortioxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet. 2018;57:673–686. doi: 10.1007/s40262-017-0612-7.
    1. Stenkrona P, Halldin C, Lundberg J. 5-HTT and 5-HT(1A) receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects. Eur Neuropsychopharmacol. 2013;23:1190–1198. doi: 10.1016/j.euroneuro.2013.01.002.
    1. Thase ME, Mahableshwarkar AR, Dragheim M, Loft H, Vieta E. A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults. Eur Neuropsychopharmacol. 2016;26:979–993. doi: 10.1016/j.euroneuro.2016.03.007.
    1. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–1366. doi: 10.1016/S0140-6736(17)32802-7.
    1. Areberg J, Sogaard B, Hojer AM. The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers. Basic Clin Pharmacol Toxicol. 2012;111:198–205. doi: 10.1111/j.1742-7843.2012.00886.x.
    1. Hvenegaard MG, Bang-Andersen B, Pedersen H, Jorgensen M, Puschl A, Dalgaard L. Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. Drug Metab Dispos. 2012;40:1357–1365. doi: 10.1124/dmd.112.044610.
    1. Chen G, Zhang W, Serenko M. Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin. J Clin Pharmacol. 2015;55:671–679. doi: 10.1002/jcph.456.
    1. Crisafulli C, Fabbri C, Porcelli S, et al. Pharmacogenetics of antidepressants. Front Pharmacol. 2011;2:6. doi: 10.3389/fphar.2011.00006.
    1. Garcia-Barcelo M, Chow LY, Lam KL, Chiu HF, Wing YK, Waye MM. Occurrence of CYP2D6 gene duplication in Hong Kong Chinese. Clin Chem. 2000;46:1411–1413.
    1. Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60:284–295.
    1. Han KM, Chang HS, Choi IK, Ham BJ, Lee MS. CYP2D6 P34S polymorphism and outcomes of escitalopram treatment in Koreans with major depression. Psychiatry Investig. 2013;10:286–293. doi: 10.4306/pi.2013.10.3.286.
    1. Lee MS. Role of genetic polymorphisms related to neurotransmitters and cytochrome P-450 enzymes in response to antidepressants. Drugs Today (Barc) 2007;43:569–581. doi: 10.1358/dot.2007.43.8.1130447.
    1. Matsuno K, Nakamura K, Aritomi Y, Nishimura A. Pharmacokinetics, safety, and tolerability of vortioxetine following single- and multiple-dose administration in healthy Japanese adults. Clin Pharmacol Drug Dev. 2018;7:319–331. doi: 10.1002/cpdd.381.
    1. Wang G, Gislum M, Filippov G, Montgomery S. Comparison of vortioxetine versus venlafaxine XR in adults in Asia with major depressive disorder: a randomized, double-blind study. Curr Med Res Opin. 2015;31:785–794. doi: 10.1185/03007995.2015.1014028.
    1. Areberg J, Petersen KB, Chen G, Naik H. Population pharmacokinetic meta-analysis of vortioxetine in healthy individuals. Basic Clin Pharmacol Toxicol. 2014;115:552–559. doi: 10.1111/bcpt.12256.
    1. Naik H, Chan S, Vakilynejad M, et al. A population pharmacokinetic-pharmacodynamic meta-analysis of vortioxetine in patients with major depressive disorder. Basic Clin Pharmacol Toxicol. 2016;118:344–355. doi: 10.1111/bcpt.12513.
    1. de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66:15–27. doi: 10.4088/JCP.v66n0103.
    1. Yin SJ, Ni YB, Wang SM, Wang X, Lou YQ, Zhang GL. Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations. J Clin Pharm Ther. 2012;37:364–369. doi: 10.1111/j.1365-2710.2011.01298.x.
    1. Davit B, Braddy AC, Conner DP, Yu LX. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences. AAPS J. 2013;15:974–990. doi: 10.1208/s12248-013-9499-x.
    1. Baldwin DS, Chrones L, Florea I, et al. The safety and tolerability of vortioxetine: analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol. 2016;30:242–252. doi: 10.1177/0269881116628440.

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