Open AccessPhysiologically‐Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan
Author(s) -
Sun Lei,
Moltke Lisa,
Rowland Yeo Karen
Publication year - 2020
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12488
Subject(s) - olanzapine , pharmacology , cyp1a2 , cyp3a4 , physiologically based pharmacokinetic modelling , pharmacokinetics , chemistry , atypical antipsychotic , clozapine , cytochrome p450 , antipsychotic drug , drug interaction , antipsychotic , medicine , metabolism , biochemistry , schizophrenia (object oriented programming) , psychiatry
A combination of the antipsychotic olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine‐associated weight gain. As cytochrome P450 (CYP) 1A2 and CYP3A4 are the major enzymes involved in metabolism of olanzapine and samidorphan, respectively, physiologically‐based pharmacokinetic (PBPK) modeling was applied to predict any drug‐drug interaction (DDI) potential between olanzapine and samidorphan or between OLZ/SAM and CYP3A4/CYP1A2 inhibitors/inducers. A PBPK model for OLZ/SAM was developed and validated by comparing model‐simulated data with observed clinical study data. Based on model‐based simulations, no DDI between olanzapine and samidorphan is expected when administered as OLZ/SAM. CYP3A4 inhibition is predicted to have a weak effect on samidorphan exposure and negligible effect on olanzapine exposure. CYP3A4 induction is predicted to reduce both samidorphan and olanzapine exposure. CYP1A2 inhibition or induction is predicted to increase or decrease, respectively, olanzapine exposure only.