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

Abstract

Introduction 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 modeling 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 modeling was performed using nonlinear mixed effects modeling in MONOLIX while the Clinical Trial Simulations were performed using R for statistical programming. The pharmacometric analysis is based from 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 modeled using an Emax model in a study population of seventy patients. Population pharmacodynamic parameters were estimated to be: Emax=85.6% (R.S.E.=3%), ED50-Men=5.15 mg/day (R.S.E.=14) and ED50-Women= 2.38 mg/day (R.S.E.=34%) with the p-value=0.037 for the gender-stratified ED50 results. Conclusion Based on the pharmacometrics analysis and model-based dosing simulations suggests that in order to achieve 70% D2RO women require a 10mg/day dose and men require approximately a 20mg/day dose of Olanzapine. Further, clinical implications exist suggesting that clinicians should factor patient gender when considering both a starting dose, as well as, a maintenance dose for patients prescribed Olanzapine due to quantifiable gender-differences of striatal dopamine D2 receptor occupancy.

The clinical course of schizophrenia in women and men—a nation-wide cohort study

“…Pharmacotherapy should certainly take gender into account, as there are sex differences in pharmacokinetics, liver enzymes and renal elimination, which necessitate doseadjustment for both oral and injectable antipsychotics. Given the sex difference in CYP enzyme activity and dopamine D2 receptor occupancy, women on average need lower dose for olanzapine and clozapine 25 . However, given their equally high risk for rehospitalization compared to men, women should not be prescribed less effective antipsychotic options.…”

Individualized medicine: Sex, hormones, genetics, and adverse drug reactions

“…In one example, women were found to require a smaller dose of olanzapine in order to achieve 70% occupancy of the dopamine D2 receptor for medication efficacy. 39 Testosterone and/or estrogen may modulate the pharmacodynamics of olanzapine at the D2 receptors as adjusting for weight, height, age, or concomitantly administered medications did not affect olanzapine clearance. 40 In addition, review of anti-obesity drugs suggests that pharmacokinetic, pharmacodynamic, and nonpharmacologic sex differences may influence success in reaching weight loss goals.…”

Sex differences in text-mined possible adverse drug events associated with drugs for psychosis

“…(Sex usually refers to biologically determined characteristics, whereas gender is a social construction; World Health Organization, 2002). However, it is well established that sex differences exist in pharmacokinetics and pharmacodynamics, influencing the response to and tolerability of drugs, including APs (Eugene and Masiak, 2017; Soldin and Mattison, 2009). Physical differences related to weight, volume of distribution and lipid mass exist, which may influence the pharmacokinetics of fat-soluble drugs, including compounds that cross the blood–brain barrier (Aichhorn et al, 2006; Barbui et al, 2005; Franconi and Campesi, 2014; Lange et al, 2017; Marazziti et al, 2013).…”