Bioequivalence of Olanzapine Given in Combination With Samidorphan as a Bilayer Tablet (ALKS 3831) Compared With Olanzapine‐Alone Tablets: Results From a Randomized, Crossover Relative Bioavailability Study

Abstract

The objective of this study was to evaluate the relative bioavailability of olanzapine in 3 olanzapine-containing tablet formulations. ALKS 3831 is a fixed-dose combination of olanzapine (OLZ, an atypical antipsychotic) and samidorphan (SAM, a μ-opioid receptor antagonist with low intrinsic activity at δ- and κ-opioid receptors), intended to provide the efficacy of OLZ while mitigating its known weight and metabolic effects. Relative bioavailability of OLZ in ALKS 3831, a bilayer tablet containing OLZ and SAM, a matching bilayer tablet containing OLZ only (OLZ), and Zyprexa (brand olanzapine [B-OLZ]) was assessed in an open-label study. Forty-eight healthy volunteers were randomly assigned to receive single oral doses of ALKS 3831 (10 mg OLZ/10 mg SAM), OLZ (10 mg OLZ), and B-OLZ (10 mg B-OLZ) on day 1 of each treatment period. Blood samples for pharmacokinetic evaluation were collected before and after each dose. Ratios of OLZ AUC , AUC , and C were compared between treatments and tested for bioequivalence, determined by 90%CIs of the geometric mean ratios (GMRs). GMRs of OLZ AUC , AUC , and C were close to 1, and the 90%CIs of the GMRs were contained within the bioequivalence limit of 80%-125% for comparison of ALKS 3831 with B-OLZ, ALKS 3831 with OLZ, and OLZ with B-OLZ, demonstrating bioequivalence of OLZ in ALKS 3831, OLZ, and B-OLZ.

Physiologically‐Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan

“…Simulated plasma concentrations and pharmacokinetic parameters were also in good agreement with observed data ( Figure ; Table ). Simulated plasma C‐T profiles of olanzapine and samidorphan following a single oral dose of OLZ/SAM in healthy subjects were consistent with observed data ( Figure ), as were simulated C‐T profiles of olanzapine and samidorphan following multiple once‐daily oral doses of OLZ/SAM 10/10 in patients with schizophrenia ( Figure ).…”

“…Simulated and observed plasma concentrations of ( a ) olanzapine and ( b ) samidorphan after 7 days of olanzapine lead‐in followed by 14 days of once‐daily oral doses of combined olanzapine and samidorphan (OLZ/SAM) 10/10 in patients with schizophrenia. a Olanzapine; b samidorphan; simulated mean (lines, n = 210) and observed individual (symbols, n = 21) plasma concentrations after 7 days of olanzapine lead‐in followed by 14 days of once‐daily oral doses of OLZ/SAM 10/10 in patients with schizophrenia. The solid line is the mean data for the simulated population, and the dotted lines are the 5th and 95th percentiles.…”

“…The two models were combined to represent administration of olanzapine and samidorphan in combination as OLZ/SAM in virtual trial simulations to ensure the same virtual individual with the exact same system/physiological parameters was administered olanzapine and samidorphan together at the same time in the same biosystem as in clinical studies with OLZ/SAM . Model‐simulated C‐T profiles well described the observed data in multiple clinical studies for model validation.…”

“…The PBPK models for olanzapine and samidorphan were first developed and verified using observed data from clinical studies in which olanzapine or samidorphan was administered alone . The models were then combined to represent administration of olanzapine and samidorphan in combination as OLZ/SAM in virtual trial simulations to ensure the same virtual individual was administered olanzapine and samidorphan together as in clinical studies with OLZ/SAM . Specifically, the PBPK models were verified by comparing simulated C‐T profiles and pharmacokinetic parameters, including C max and AUC, for olanzapine and/or samidorphan with observed data obtained from clinical studies .…”

“…The primary metabolic pathways for olanzapine are direct glucuronidation via uridine 5'‐diphospho‐glucuronosyltransferase 1A4 and cytochrome P450 (CYP)‐mediated oxidation, mainly by CYP1A2 with minor contributions from CYP2C8, CYP3A4, and CYP2D6 . Samidorphan is eliminated primarily via CYP3A4‐mediated hepatic metabolism and renal excretion …”