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Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status

  • Marit TveitoEmail author
  • Espen Molden
  • Gudrun Høiseth
  • Christoph U. Correll
  • Robert Løvsletten Smith
Pharmacogenetics
  • 96 Downloads

Abstract

Purpose

Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole.

Methods

Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation.

Results

We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups.

Conclusions

In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.

Keywords

Aripiprazole Genotype CYP2D6 Age Therapeutic drug monitoring Long-acting injection 

Notes

Author contributions

Marit Tveito designed the research, analyzed the data, and wrote the manuscript.

Espen Molden designed the research and wrote the manuscript.

Gudrun Høiseth designed the research and wrote the manuscript.

Cristoph U. Correll wrote the manuscript.

Robert L. Smith analyzed data and wrote the manuscript.

Funding information

This work was funded by the South-Eastern Norway Regional Health Authority (grant numbers 2017085 and 2016097).

Compliance with ethical standards

Conflict of interest

Dr. Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gerson Lehrman Group, Indivior, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. Prof. Molden has received speaker´s honoraria from Lundbeck and Lilly. The other authors have no conflicts of interest to declare.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for PsychopharmacologyDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway
  3. 3.Department of Forensic SciencesOslo University HospitalOsloNorway
  4. 4.Department of Psychiatry, Northwell HealthThe Zucker Hillside HospitalGlen OaksUSA
  5. 5.Department of Psychiatry and Molecular MedicineHofstra Northwell School of MedicineHempsteadUSA
  6. 6.Department of Child and Adolescent PsychiatryCharité UniversitätsmedizinBerlinGermany

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