A combination of
olanzapine and
samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with
schizophrenia or bipolar I disorder. Population pharmacokinetic models for
olanzapine and
samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with
schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both
olanzapine and
samidorphan. Age, sex, race, smoking status, and
body weight were identified as covariates that impacted the pharmacokinetics of
olanzapine. A moderate effect of
body weight on
samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with
rifampin on the pharmacokinetics of
olanzapine and
samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of
olanzapine or
samidorphan. Consistent with the known metabolic pathways for
olanzapine (primarily via
uridine 5'-diphospho-
glucuronosyltransferase-mediated direct glucuronidation and
cytochrome P450 [CYP]-mediated oxidation) and for
samidorphan (predominantly mediated by
CYP3A4), coadministration of
olanzapine and
samidorphan with
rifampin, a strong inducer of
CYP3A4 and an inducer of
uridine 5'-diphospho-glucuronosyltransferase
enzymes, significantly decreased the systemic exposure of both
olanzapine and
samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in
olanzapine and
samidorphan exposure.