<p>Effect of hepatic and renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination as a bilayer tablet</p>

Abstract

BackgroundA combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain.MethodsTwo multicenter, open-label, parallel-cohort studies were performed to evaluate the effect of moderate hepatic impairment (Child-Pugh score 7–9 [class B]; study 1) and severe renal impairment (estimated glomerular filtration rate: 15–29 mL/min/1.73 m2; study 2) on the pharmacokinetics, safety, and tolerability of a single dose of OLZ/SAM 5/10 mg.ResultsThere was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and a 2.17-fold increase in maximum plasma concentration (Cmax) of olanzapine, and a 1.52-fold increase in AUC0-∞ and a 1.63-fold increase in Cmax of samidorphan, in subjects with moderate hepatic impairment compared with healthy control subjects. Compared with healthy control subjects, subjects with severe renal impairment had a 33% and 56% reduction in clearance, a 1.51- and 2.31-fold increase in AUC0-∞, and a 1.32- and 1.37-fold increase in Cmax of olanzapine and samidorphan, respectively.ConclusionOLZ/SAM 5/10 mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.

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

“…Based on geometric mean data, the model predicted a 1.5fold increase in the total exposure (AUC 0-∞ ) of olanzapine in subjects with severe RI compared with healthy controls, which was consistent with the 1.5-fold increase observed in the clinical study [16]. Similarly, the model predicted a 2.2fold increase in the AUC 0-∞ of samidorphan in subjects with severe RI, consistent with the 2.3-fold increase observed in the clinical study [16]. Model-predicted reductions of 38% and 54% in olanzapine and samidorphan total clearance, respectively, in subjects with severe RI, were also consistent with the reductions of 33% and 56%, respectively, observed in the clinical study [16].…”

“…The model also well predicted the observed plasma exposure (C max and AUC) of olanzapine (within 10%) and samidorphan (within 50%) following multiple-dose administration of OLZ/SAM 10/10 or 20/10 in patients with schizophrenia [13]. The PBPK model for OLZ/SAM was further validated using observed data obtained from the clinical study evaluating the impact of severe RI on the pharmacokinetics of olanzapine and samidorphan [16]. The predicted increases in olanzapine and samidorphan AUC 0-∞ (1.5-and 2.2-fold, respectively) in subjects with severe RI relative to healthy age-matched subjects with normal renal function corresponded with decreases in their respective total clearance (38% and 54%).…”

“…AUC area under the concentration-time curve, C max maximum concentration, OLZ/SAM combination of olanzapine and samidorphan, RI renal impairment, t ½ half-life and samidorphan exposures, with < 1.5-fold increases in C max,ss and AUC τ,ss , whereas moderate-to-severe RI resulted in up to 1.5-fold increases in C max,ss and up to a 2.2-fold increase in AUC τ,ss of olanzapine and samidorphan relative to subjects with normal renal function. Although increases in fu with increasing severity of RI were initially predicted for olanzapine (0.071-0.088) and samidorphan (0.69-0.74), data from the clinical study indicated that the fu value for olanzapine was similar in subjects with severe RI and in healthy controls with normal renal function [16]. Therefore, in the current modeling predictions, the fu value was fixed for both olanzapine and samidorphan and was assumed to be the same in healthy subjects and across all categories of RI, which allowed improved recovery of the observed change in exposure for both olanzapine and samidorphan in subjects with severe RI.…”

“…Olanzapine is mainly eliminated via direct glucuronidation and cytochrome P450 (CYP)-mediated hepatic metabolism; only 7% of the administered dose is excreted renally as unchanged olanzapine [ 15 ]. Samidorphan is eliminated primarily via CYP3A4-mediated hepatic metabolism, with approximately 20% of the administered dose being excreted renally as unchanged samidorphan [ 16 ]. It was of interest to investigate the effect of renal impairment (RI) on the pharmacokinetics of olanzapine and samidorphan because schizophrenia and bipolar disorder have been associated with increased risks of chronic kidney disease (CKD) [ 17 , 18 ], and RI can affect the clearance of both renally and non-renally cleared drugs [ 19 , 20 ].…”

“…However, given that the concept of using PBPK modeling to prospectively predict drug pharmacokinetics in subjects with RI has not been systematically established [ 21 ], a clinical study was conducted to evaluate the effect of RI and to verify the PBPK modeling predictions. Because neither olanzapine nor samidorphan is predominantly renally eliminated, only severe RI was evaluated in the clinical study [ 16 ], where any change in clearance would be most pronounced.…”