Using physiologically‐based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically‐based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once‐daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady‐state total systemic exposures by 1.1‐, 1.5‐, and 1.6‐fold, respectively, for olanzapine, and by 1.2‐, 1.9‐, and 2.3‐fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.