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

Abstract

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.

Effects of 5‐HT₃ receptor antagonists on cisplatin‐induced kidney injury

“… 34 , 35 Data on the proportion of patients using other antiemetic agents, such as NK1R antagonists, olanzapine, were not obtained because these drugs do not affect renal function in patients with an eGFR of greater than or equal to 60 ml/min/1.73 m 2 . 36 , 37 , 38 , 39 …”

“…agents, such as NK1R antagonists, olanzapine, were not obtained because these drugs do not affect renal function in patients with an eGFR of ≥60 mL/min/1.73 m 2 [36][37][38][39].…”

An Integrated Approach for Assessing the Impact of Renal Impairment on Pharmacokinetics of Drugs in Development: Pivotal Role of PBPK Modelling

“…Key changes in physiological parameters reflecting the effects of RI, included reductions in CYP enzymes, an increase in albumin and a decrease in α‐acid‐glycoprotein levels. 8 Thus, if a drug binds mainly to albumin, the increased unbound fraction in plasma often observed in patients with RI, can to some extent, cancel out the effects of the reduction in CYP activity on total drug exposures. This mainly affects highly bound drugs; 36% of the compounds in the dataset were > 95% bound.…”

“…Indeed, such an approach was used to evaluate the effect of RI on a combination of the antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) in development for the treatment of patients with schizophrenia or bipolar I disorder. 8 Both OLZ and SAM are mainly cleared via CYP‐mediated metabolism with renal clearance contributions of 10 and 20%, respectively. During clinical development, it was of interest to investigate the effect of RI on the PKs of both drugs, as kidney disease is a comorbidity in some patients requiring treatment with antipsychotic medications.…”

“…High fidelity PBPK models, developed initially for assessment of the DDI liability of OLZ/SAM, were used to predict the effects of RI on the single‐dose (SD) exposure of both drugs; increases > 1.5‐fold were indicated in patients with moderate and severe RI. 8 Thereafter, an SD clinical study was conducted to assess the effects of severe RI on OLZ/SAM as well as to inform the PBPK model prior to prospective simulations of multiple doses in patients with varying degrees of RI. After integration of ex vivo unbound fraction values from the clinical study, the PBPK models predicted reductions of 38% and 54% in OLZ and SAM total clearance, respectively, and AUC ratios of 1.5‐fold and 2.2‐fold in subjects with severe RI relative to healthy controls, which were entirely consistent with observed data.…”