Olanzapine is a highly effective antipsychotic, but its uses are limited by the risk of significant weight gain and metabolic effects. A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) was recently approved in the United States for the treatment of adults with schizophrenia and bipolar I disorder. OLZ/SAM provides the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Physiologically-based pharmacokinetic (PBPK) modeling was used to assess the drug-drug interaction (DDI) potential of OLZ/SAM as well as to inform dosing in special populations, including smokers and those with organ impairment. The focus of the presentation was on leveraging PBPK modeling during the development of OLZ/SAM and regulatory interactions.