Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder - what is it, and will it be used?

Faden, Justin; Serdenes, Ryan; Citrome, Leslie

doi:10.1080/14737175.2022.2060742

Cited by 5 publications

(7 citation statements)

References 102 publications

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“… 43 , 47 Of note, for both olanzapine combination preparations with fluoxetine (Symbyax) and samidorphan (Lybalvi) there are no clinically significant pharmacokinetic differences when compared to olanzapine monotherapy. 19 , 48 , 49 …”

Section: Available Formulations and Pharmacokinetic Differencesmentioning

confidence: 99%

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Olanzapine Pharmacokinetics: A Clinical Review of Current Insights and Remaining Questions

Kolli,

Kelley,

Rosales

et al. 2023

PGPM

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Olanzapine is one of the most widely used antipsychotics since its initial approval by the US Food and Drug Administration in 1996 and has undergone extensive pharmacokinetic study. Despite being utilized in clinical psychiatry for decades, there remain questions regarding the variety of available formulations, the utility of therapeutic drug monitoring, altered kinetic properties in special populations/medical illnesses, the use of high-dose olanzapine, and drug interactions, among many others. We performed a narrative literature review of olanzapine pharmacokinetics in June 2023 using the US National Library of Medicine’s PubMed.gov resource ( https://www.ncbi.nlm.nih.gov/pubmed ) and Google Scholar. Herein, we review clinically relevant aspects of olanzapine pharmacokinetic data while highlighting knowledge gaps and potential areas of future study.

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Section: Available Formulations and Pharmacokinetic Differencesmentioning

confidence: 99%

“… 15–18 Although, olanzapine-samidorphan was recently approved for the treatment of schizophrenia and bipolar disorder and has shown efficacy in partially ameliorating olanzapine-induced weight gain. 19 …”

Section: Introductionmentioning

confidence: 99%

Olanzapine Pharmacokinetics: A Clinical Review of Current Insights and Remaining Questions

Kolli,

Kelley,

Rosales

et al. 2023

PGPM

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“… 1 , 5 , 6 OLZ/SAM therefore may provide a treatment option for patients who would benefit from olanzapine, with a reduced risk of significant weight gain. 7 , 8 …”

Section: Introductionmentioning

confidence: 99%

“…1,5,6 OLZ/SAM therefore may provide a treatment option for patients who would benefit from olanzapine, with a reduced risk of significant weight gain. 7,8 The opioid receptor system consists of mu, delta, and kappa receptors (MOR, DOR, and KOR, respectively), and each plays a distinct role in the regulation of weight and metabolism. [9][10][11][12] In studies examining the effects of OLZ/SAM in rats and nonhuman primates, the addition of samidorphan to olanzapine attenuated olanzapine-associated weight gain, increases in adiposity, and insulin insensitivity.…”

Section: Introductionmentioning

confidence: 99%

In vivo Characterization of the Opioid Receptor–Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations

Tan¹,

Gajipara²,

Sun³

et al. 2022

NDT

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Introduction The atypical antipsychotic olanzapine is approved for the treatment of schizophrenia and bipolar I disorder; however, weight gain and metabolic dysregulation associated with olanzapine therapy have limited its clinical utility. In clinical studies, treatment with the combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain while providing antipsychotic efficacy similar to that of olanzapine. Although samidorphan is structurally similar to the opioid receptor antagonist naltrexone, the two differ in their pharmacokinetics and in vitro binding affinities to mu, delta, and kappa opioid receptors (MOR, DOR, and KOR, respectively). The objective of this series of nonclinical studies was to compare the in vivo binding profiles of samidorphan and naltrexone and their receptor occupancies at MOR, DOR, and KOR in rat brains. Methods Male rats were injected with samidorphan or naltrexone to obtain total and unbound plasma and brain concentrations representing levels observed in humans at clinically relevant oral doses. Subsequently, samidorphan and naltrexone brain receptor occupancy at MOR, DOR, and KOR was measured using ultra-performance liquid chromatography and high-resolution accurate-mass mass spectrometry. Results A dose-dependent increase in samidorphan occupancy was observed at MOR, DOR, and KOR (EC 50 : 5.1, 54.7, and 42.9 nM, respectively). Occupancy of naltrexone at MOR (EC 50 : 15.5 nM) and KOR was dose dependent; minimal DOR occupancy was detected. At the clinically relevant unbound brain concentration of 23.1 nM, samidorphan bound to MOR, DOR, and KOR with 93.2%, 36.1%, and 41.9% occupancy, respectively. At 33.5 nM, naltrexone bound to MOR and KOR with 79.4% and 9.4% occupancy, respectively, with no binding at DOR. Discussion At clinically relevant concentrations, samidorphan occupied MOR, DOR, and KOR, whereas naltrexone occupied only MOR and KOR. The binding profile of samidorphan differs from that of naltrexone, with potential clinical implications.

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“…Pharmacological agents are being investigated to further improve the metabolic side effect profile of SGAs. For example, the recent FDA-approved combination of olanzapine and samidorphan for the treatment of schizophrenia and BD has been shown to mitigate antipsychotic-associated weight gain 31 . It would have been ideal if the DCGI had waited for more evidence in favor of endoxifen before giving its approval for marketing of this drug in India.…”

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Endoxifen Approval for Bipolar Disorder in India

Gupta

Singh

2023

J Clin Psychopharmacol

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Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder - what is it, and will it be used?

Cited by 5 publications

References 102 publications

Olanzapine Pharmacokinetics: A Clinical Review of Current Insights and Remaining Questions

Olanzapine Pharmacokinetics: A Clinical Review of Current Insights and Remaining Questions

In vivo Characterization of the Opioid Receptor–Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations

Endoxifen Approval for Bipolar Disorder in India

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