Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia

Martin, William; Correll, Christoph U.; Weiden, Peter J.; Jiang, Ying; Pathak, Sanjeev; DiPetrillo, Lauren; Silverman, Bernard L.; Ehrich, Elliot W.

doi:10.1176/appi.ajp.2018.18030280

Cited by 69 publications

(107 citation statements)

References 39 publications

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“…In a phase 1 study in healthy adults, less weight gain was observed in subjects who received a combination of OLZ (10 mg) and SAM (5 mg) compared with subjects who received OLZ (10 mg) alone . In a subsequent phase 2 study, coadministration of OLZ with SAM (5, 10, and 20 mg) mitigated OLZ‐induced weight gain in adults with schizophrenia . In addition to being developed in combination with OLZ for the treatment of schizophrenia, SAM (at a 2‐mg dose) is also under evaluation in a fixed‐dose combination with buprenorphine for a proposed indication as adjunctive treatment of major depressive disorder …”

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confidence: 99%

“…6 In a subsequent phase 2 study, coadministration of OLZ with SAM (5, 10, and 20 mg) mitigated OLZ-induced weight gain in adults with schizophrenia. 7 In addition to being developed in combination with OLZ for the treatment of schizophrenia, SAM (at a 2-mg dose) is also under evaluation in a fixed-dose combination with buprenorphine for a proposed indication as adjunctive treatment of major depressive disorder. 8 OLZ/SAM is formulated as an immediate-release bilayer tablet for once-daily oral administration, with one layer containing OLZ and the other layer containing SAM.…”

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confidence: 99%

“…8 OLZ/SAM is formulated as an immediate-release bilayer tablet for once-daily oral administration, with one layer containing OLZ and the other layer containing SAM. 7 A fixed dose of 10 mg SAM in combination with multiple dose strengths of OLZ (5,10,15, and 20 mg) was selected for further investigation in phase 3 studies based on the risk/benefit ratio for weight mitigation and safety profile.…”

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confidence: 99%

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Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan

Sun

McDonnell

et al. 2019

Clinical Pharm in Drug Dev

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ALKS 3831 is a combination of olanzapine and samidorphan (OLZ/SAM), intended to provide the antipsychotic efficacy of OLZ while mitigating its known weight gain and metabolic effects. This randomized, 2‐way crossover study evaluated the effect of food on the pharmacokinetics (PK) of OLZ and SAM (both are Biopharmaceutics Classification System class 3 compounds) given in combination as OLZ/SAM. Thirty‐six healthy volunteers were randomized to receive a single dose of OLZ/SAM (10 mg OLZ/10 mg SAM) in either fasted or fed conditions. After a 14‐day washout period, study participants received the same OLZ/SAM dose in the opposite condition. PK profiles of OLZ and SAM were similar in fed and fasted conditions. The 90% confidence intervals (CIs) for the fed/fasted ratio of the geometric means for OLZ AUC0‐∞ and Cmax and SAM AUC0‐∞ were within the equivalence limit of 80%‐125%. Although the lower bound of the 90%CI for the fed/fasted ratio of SAM Cmax (76%‐94%) was slightly below the 80% equivalence limit, this slight decrease was not considered clinically meaningful. The results indicated that food does not have a clinically relevant impact on the PK of OLZ and SAM given as OLZ/SAM.

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Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan

Sun

McDonnell

et al. 2019

Clinical Pharm in Drug Dev

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“…In a phase 1 study in healthy volunteers, weight gain was significantly lower in those treated with OLZ/SAM than those treated with olanzapine monotherapy. 20 In a subsequent phase 2 study 21 in patients with schizophrenia who were clinically stable (defined as a Positive and Negative Syndrome Scale [PANSS] score ≤ 80 and a Clinical Global Impressions-Severity of Illness Scale [CGI-S] score ≤ 3 at screening), the antipsychotic efficacy of OLZ/SAM was similar to that of olanzapine; the presence of samidorphan mitigated olanzapine-associated weight gain, although a difference in weight gain was not observed until after 4 weeks of treatment.…”

Section: E2mentioning

confidence: 99%

Efficacy and Safety of a Combination of Olanzapine and Samidorphan in Adult Patients With an Acute Exacerbation of Schizophrenia

Potkin¹,

Kunovac²,

Silverman³

et al. 2020

J. Clin. Psychiatry

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Objective: To assess the antipsychotic efficacy and safety of a combination of olanzapine and samidorphan (OLZ/SAM). Methods: This 4-week, phase 3, randomized, double-blind, placeboand olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation. Patients were randomized 1:1:1 to OLZ/SAM, olanzapine monotherapy, or placebo. The primary and key secondary efficacy endpoint assessed was the change in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness Scale (CGI-S) score between baseline and week 4, respectively, for OLZ/SAM versus placebo. Safety monitoring occurred throughout. Results: 401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: −6.4 ± 1.8 [P < .001] and −0.38 ± 0.12 [P = .002], respectively). Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of −5.3 ± 1.84 [P = .004] and −0.44 ± 0.12 [P < .001], respectively). Adverse events (AEs) occurred in 54.5%, 54.9%, and 44.8% of patients on OLZ/SAM, olanzapine, and placebo, respectively. Weight gain, somnolence, dry mouth, anxiety, and headache were the most common AEs (ie, ≥ 5%) with active treatment. Conclusions: OLZ/SAM treatment resulted in statistically and clinically significant efficacy improvements over 4 weeks versus placebo in adults with acutely exacerbated schizophrenia. Improvements were similar to those observed with olanzapine. OLZ/SAM was well tolerated, with a safety profile similar to that of olanzapine.

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“…10,11 In vivo, it has been established that samidorphan functions as an opioid receptor antagonist. 12 In studies enrolling healthy adult subjects 13 and adult patients with schizophrenia, 14 the presence of samidorphan limited olanzapine-induced weight gain in those receiving OLZ/SAM vs. olanzapine alone.…”

mentioning

confidence: 99%

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

Sun

Moltke

Yeo

2020

CPT Pharmacom & Syst Pharma

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A combination of the antipsychotic olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine‐associated weight gain. As cytochrome P450 (CYP) 1A2 and CYP3A4 are the major enzymes involved in metabolism of olanzapine and samidorphan, respectively, physiologically‐based pharmacokinetic (PBPK) modeling was applied to predict any drug‐drug interaction (DDI) potential between olanzapine and samidorphan or between OLZ/SAM and CYP3A4/CYP1A2 inhibitors/inducers. A PBPK model for OLZ/SAM was developed and validated by comparing model‐simulated data with observed clinical study data. Based on model‐based simulations, no DDI between olanzapine and samidorphan is expected when administered as OLZ/SAM. CYP3A4 inhibition is predicted to have a weak effect on samidorphan exposure and negligible effect on olanzapine exposure. CYP3A4 induction is predicted to reduce both samidorphan and olanzapine exposure. CYP1A2 inhibition or induction is predicted to increase or decrease, respectively, olanzapine exposure only.

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Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia

Cited by 69 publications

References 39 publications

Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan

Effect of Food on the Pharmacokinetics of a Combination of Olanzapine and Samidorphan

Efficacy and Safety of a Combination of Olanzapine and Samidorphan in Adult Patients With an Acute Exacerbation of Schizophrenia

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

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