European Journal of Clinical Pharmacology

, Volume 74, Issue 5, pp 593–599 | Cite as

Determination of plasma concentration reference ranges for oral aripiprazole, olanzapine, and quetiapine

  • Julia Korell
  • Bruce Green
  • Allan Rae
  • Bart Remmerie
  • An Vermeulen
Pharmacokinetics and Disposition
  • 129 Downloads

Abstract

Background

Schizophrenia is a common disease which is commonly managed using antipsychotic medications (APS). Inadequate response and lack of adherence often prevent optimal therapeutic effectiveness. Monitoring APS concentrations can be useful to help improve outcomes for the patient.

Aims

The aim of this study was to develop “reference ranges” for oral aripiprazole, olanzapine, and quetiapine to allow clinicians to understand expected variability in patients treated with APS. The reference ranges were constructed to account for different oral doses, sampling times, and variability both between, and within, subjects.

Methods

Population pharmacokinetic models were used to simulate plasma concentrations over time under different doses and population demographics. The references were validated against external data both numerically and graphically.

Results

Reference ranges for oral aripiprazole, olanzapine, and quetiapine were derived and successfully validated against the external data. The 80% reference range for aripiprazole following a 2-mg oral dose was 14.7–41.6 ng/mL 0–4 h post dose and 10.6–37.1 ng/mL 20–24 h post dose. These ranges increased to 221–624 ng/mL 0–4 h post dose following administration of a 30-mg dose, and 159–557 ng/mL 20–24 h post dose. The 80% reference range 0–4 h post dose was 22.5–67.1 ng/mL following a 15-mg dose once daily of oral olanzapine, and 179–768 ng/mL following a 150-mg dose once daily of oral quetiapine.

Conclusions

Comparing individual patients’ APS levels with reference ranges, along with a full clinical assessment, could provide important insights to help a clinician optimize APS therapy.

Keywords

Antipsychotics Routine clinical care Nonlinear mixed effects models Reference ranges Simulations 

Notes

Acknowledgements

The authors acknowledge the help of Mr. Simon Leung for his contributions to materials presented in this manuscript.

Author contributions

Julia Korell (JK), Allan Rae (AR), and Bruce Green (BG) performed the research and wrote the initial draft of the manuscript in collaboration with An Vermeulen (AV) and Bart Remmerie (BR). All authors contributed towards development of the reference ranges, with BG, JK, and AV responsible for the population PK model development and evaluations with support from AR.

Compliance with ethical standards

Conflict of interest

Bruce Green, Julia Korell, and Allan Rae are employees of Model Answers Pty Ltd., which received financial reimbursement from Janssen R&D.

An Vermeulen and Bart Remmerie are employees of Janssen R&D, which sponsored this research.

Supplementary material

228_2018_2419_MOESM1_ESM.pdf (102 kb)
ESM 1 (PDF 102 kb)
228_2018_2419_MOESM2_ESM.pdf (903 kb)
ESM 2 (PDF 903 kb)
228_2018_2419_MOESM3_ESM.pdf (212 kb)
ESM 3 (PDF 211 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Julia Korell
    • 1
  • Bruce Green
    • 1
  • Allan Rae
    • 1
  • Bart Remmerie
    • 2
  • An Vermeulen
    • 2
  1. 1.Model Answers Pty LtdBrisbaneAustralia
  2. 2.Janssen R&DJanssen Pharmaceutica NVBeerseBelgium

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