A pharmacodynamic modelling and simulation study identifying gender differences of daily olanzapine dose and dopamine D2-receptor occupancy

Abstract

Background: Gender differences in treatment response rates for patients treated with antipsychotics are known. However, the literature lacks a pharmacodynamic model to allow for gender-based clinical trial simulations from modelling parameters for Olanzapine and dopamine D2 receptor occupancy. Thus, the primary aim of this analysis is to test and quantify the effect of gender on the pharmacodynamics of Olanzapine.

Methods: Population pharmacodynamic modelling was performed using non-linear mixed effects modelling in MONOLIX, while the Clinical Trial Simulations were performed using R for statistical programming. The pharmacometric analysis is based on a pooled data approach from three clinical studies where patients were diagnosed with schizophrenia and one clinical study where the patients were diagnosed with bipolar disorder.

Results: Olanzapine D2RO was modelled using an E_max model in a study population of 70 patients. Population pharmacodynamic parameters were estimated to be: E_max = 85.6% (RSE = 3%), ED50-Men = 5.15 mg/day (RSE = 14) and ED50-Women = 2.38 mg/day (RSE = 34%), with the p-value = 0.037 for the gender-stratified ED50 results.

Conclusion: The pharmacometrics analysis and model-based dosing simulations suggest that, in order to achieve 70% D2RO, women require a 10 mg/day dose and men require approximately a 20 mg/day dose of Olanzapine. Further, clinical implications exist suggesting that clinicians should factor patient gender when considering both a starting dose, as well a, a maintenance dose for patients prescribed Olanzapine due to quantifiable gender-differences of striatal dopamine D2 receptor occupancy.

Keywords:

• Olanzapine
• gender differences
• pharmacodynamics
• dopamine
• D2RO
• psychiatry

Acknowledgements

We would like to thank Dr B. Eugene for help with the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685.