Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effect of Renal Impairment on the Pharmacokinetics of Olanzapine and Samidorphan Given in Combination.

Background: A combination of the antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of patients with schizophrenia or bipolar I disorder. The effect of severe renal impairment on the pharmacokinetics of olanzapine and samidorphan after a single oral dose of OLZ/SAM was evaluated in a clinical study. Complementary to the clinical findings, physiologically based pharmacokinetic modeling was used to assess the effects of varying degrees of renal impairment on the pharmacokinetics of olanzapine and samidorphan.

Methods: A physiologically based pharmacokinetic model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical data. The model was applied to predict changes in olanzapine and samidorphan pharmacokinetics after administration of OLZ/SAM in subjects with mild, moderate, and severe renal impairment relative to age-matched controls with normal renal function.

Results: The model predicted 1.5- and 2.2-fold increases in olanzapine and samidorphan area under the plasma concentration-time curve (AUC), respectively, after a single dose of OLZ/SAM in subjects with severe renal impairment vs controls, which was consistent with results from the clinical study. Application of the model prediction indicated increases in steady-state olanzapine AUC of 1.2-, 1.5-, and 1.6-fold, and samidorphan AUC of 1.4-, 1.8-, and 2.2-fold, in subjects with mild, moderate, and severe renal impairment, respectively, relative to healthy controls.

Conclusions: Physiologically based pharmacokinetic modeling extended the findings from a clinical study in severe renal impairment to other untested clinical scenarios; these data could be of interest to clinicians treating patients with renal impairment.