Pharmacokinetic-Pharmacodynamic Analysis of Concentration-Response Relationship in Schizophrenia Patients Treated with Olanzapine or OLZ/SAM

Abstract

Background

A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the Food and Drug Administration for the treatment of schizophrenia and bipolar I disorder. This exploratory population pharmacokinetic-pharmacodynamic analysis evaluated potential relationships between drug exposure and treatment effects.

Methods

Positive and Negative Syndrome Scale (PANSS) total score and/or bodyweight data from efficacy studies served as pharmacodynamic endpoints. Pharmacokinetic input came from predicted plasma drug concentrations using a population pharmacokinetic model for the corresponding studies. Regression and box plots were generated to investigate potential pharmacokinetic-pharmacodynamic relationships.

Results

PANSS total score and/or bodyweight records were paired with olanzapine and/or samidorphan concentrations from 1464 patients with schizophrenia. Within the clinical dose range for olanzapine (10-20 mg/day) and samidorphan (5-20 mg/day), no significant correlation was noted between (a) olanzapine concentrations and change in PANSS total score, or % change in body weight, in patients treated with OLZ/SAM or olanzapine, and (b) samidorphan concentration or samidorphan-to-olanzapine concentration ratio and % change in body weight. No meaningful difference in olanzapine and samidorphan concentrations or samidorphan-to-olanzapine concentration ratios was observed between patients with <10% and ≥10% weight gain.

Conclusions

The antipsychotic efficacy of olanzapine was not affected by samidorphan at any concentration of olanzapine. Furthermore, olanzapine-associated weight gain did not correlate with olanzapine dose or plasma concentration. Finally, the effect of OLZ/SAM on mitigation of olanzapine-associated weight gain was not affected by intersubject variability in olanzapine and/or samidorphan plasma concentrations.

Funding

Alkermes, Inc.