Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data.

Szczegóły
Abstrakt

Tytuł:: Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data.
Autorzy:: Frederiksen T; PK/PD Modelling and Simulation, H. Lundbeck A/S, Ottiliavej 9, Valby, Denmark. .; Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark. .
Smith RL; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Wollmann BM; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Areberg J; PK/PD Modelling and Simulation, H. Lundbeck A/S, Ottiliavej 9, Valby, Denmark.
Molden E; Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.; Department of Pharmacy, University of Oslo, Oslo, Norway.
Źródło:: Clinical pharmacokinetics [Clin Pharmacokinet] 2021 Nov; Vol. 60 (11), pp. 1475-1486. Date of Electronic Publication: 2021 Jun 14.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: [Switzerland] : Adis, part of Springer Science+Business Media
Original Publication: New York, ADIS Press.
MeSH Terms:: Cytochrome P-450 CYP2D6*/genetics
Drug Monitoring*
Genotype ; Humans ; Retrospective Studies ; Vortioxetine
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Grant Information:: 8053-00083B Innovationsfonden
Substance Nomenclature:: 3O2K1S3WQV (Vortioxetine)
EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
Entry Date(s):: Date Created: 20210614 Date Completed: 20211125 Latest Revision: 20220907
Update Code:: 20240105
PubMed Central ID:: PMC8585800
DOI:: 10.1007/s40262-021-01029-7
PMID:: 34121163
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Introduction: Vortioxetine is an antidepressant primarily metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2D6. A population pharmacokinetic (popPK) model of vortioxetine and its CYP2D6-dependent metabolite was recently published.
Objective: The aim of the current study was to assess the predictive performance of the popPK model using vortioxetine concentration measurements from a clinical setting. Furthermore, the study aimed to evaluate the ability of different CYP2D6 phenotype classification systems to provide accurate concentration predictions.
Methods: Overall, 1388 patients receiving vortioxetine treatment were identified from a therapeutic drug monitoring (TDM) database in Oslo, Norway; 334 CYP2D6-genotyped patients with 502 serum concentrations of vortioxetine, analysed by a validated ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method, were retrospectively included. The performance of the vortioxetine popPK model was tested on the clinical data from the TDM database.
Results: Overall, the model had a good ability to predict vortioxetine concentrations measured in clinical practice, with a slight tendency to overpredict concentrations. Using simulation-based diagnostics, 76% of the prediction-corrected TDM concentrations were within the 90% prediction interval based on 1000 simulated data sets. Prediction-based diagnostics showed the best performance for CYP2D6 poor and ultrarapid metabolizers, with a median prediction error (MDPE) of 12% and 23%, respectively, while the poorest performance was observed for normal metabolizers, with an MDPE of 66%. In the comparison of different CYP2D6 phenotype classification systems, the use of differentiated activity scores for decreased function alleles did not improve the concentration predictions. Grouping the CYP2D6 genotypes into the four conventional phenotype groups provided predictions closest to the TDM measured concentrations.
Conclusion: TDM data provide a unique insight into real-world clinical practice with vortioxetine. The tendency of the popPK model to overpredict vortioxetine concentrations measured in TDM may be attributed to several factors, including poor treatment compliance for some patients and, to a lesser extent, lack of information on patient characteristics and misspecified CYP2D6 alleles. To optimize personalized therapy with vortioxetine, real-world clinical data sets originating from different ethnicities need to be studied in the future.
(© 2021. The Author(s).)

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