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: D2RO; Olanzapine; dopamine; gender differences; pharmacodynamics; psychiatry.

Figure 1. Observed versus Predicted Plots

Goodness-of-fit plots for the observed versus predicted model diagnostics of the population (a) fit and the individual (b) fit for the Olanzapine D2 Receptor Occupancy.

Figure 2. Weighted Residual Plots

Goodness-of-Fit plots illustrating the individual weighted residuals (IWRES) (a) and the normalized prediction distribution errors (NPDE) over time (b) and the IWRES (c) and NPDE over the predicted D2 Receptor Occupancy (d). The bottom two graphs illustrate the probability density function distributions for the IWRES (e) and NPDE (f).

Figure 3. Visual Predictive Check

The Visual Predictive Check for the final population pharmacodynamic model for D2 receptor occupancy illustrating percentile distribution bands. The solid green lines represent the 90^th (upper green), 50^th (middle green) and 10^th (bottom green) percentiles. The upper and lower blue shaded are represent the 95% confidence interval for the 90^th and 10^th percentiles, while the middle peach band shaded band represents the 95% confidence interval for the population median predictions.

Figure 4. Dose Response Simulations

Simulation results illustrating gender-stratified Olanzapine doses (mg/day) and the corresponding dopamine D2 receptor occupancy (%) levels. The ED50-Female=2.38 mg/day while the ED50-Male=5.15 mg/day. The solid line represents the average population receptor occupancy profile while the shaded bands represent the 95% confidence intervals for the population mean.

Figure 5. Olanzapine Pharmacokinetic Dosing Simulations

Simulated concentration-time curves for virtual populations of 4000 men (top) and 4000 women (bottom) administered 14-days of Olanzapine at the average doses calculated from the pooled data included in the four studies.