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Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia.

ABSTRACT: A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

SUBMITTER: Sun L

PROVIDER: S-EPMC8596792 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionSchizophrenia is a complex medical illness characterized by hallucinations, delusions, and cognitive issues. Olanzapine, a second-generation antipsychotic widely prescribed for schizophrenia has proven to be efficacious, however, its use is associated with major adverse effects such as weight gain, metabolic syndrome and diabetes mellitus. Recently, FDA approved a combination dose of olanzapine and samidorphan (OLZ/SAM) to mitigate the adverse outcomes associated with olanzapine use for the treatment of Schizophrenia.ObjectivesThe approval of olanzapine/samidorphan combination by FDA in treatment of schizophrenia and bipolar I disorder has been a milestone. This article summarizes the clinical trials reporting the clinical efficacy and adverse effects of olanzapine/samidorphan combination along with their bias assessment.MethodsPubmed, science direct, Ovid SP and Google Scholar were comprehensively searched for data collection. Clinical trials reporting the efficacy and adverse outcomes of the OLZ/SAM regimen were included in the review and the Cochrane risk of bias assessment tool (RoB 2.0, version 2019) was used to assess the risk of bias in each study.ResultsFive trials employed the use of Positive and Negative Syndrome Scales (PANSS) and Clinical Global Impression-Severity (CGI-S) scale to assess the efficacy of OLZ/SAM. Overall, OLZ/SAM showed a significant reduction in PANSS total scores and CGI-S scores and might be a viable option for long-term treatment. The safety of combined therapy is assessed by trials considering the factors of ECG parameters, suicidal events, and movement disorders. Major adverse events included nervous system disorders, changes in blood chemistry, and metabolic or nutritional disorders, with worsening of adverse outcomes observed in a total of nineteen cases in six studies.ConclusionThe FDA-approved drug recombination of OLZ/SAM for the treatment of schizophrenia revealed efficacious outcomes and was generally well tolerated by patients partaking in various trials. The potential of samidorphan in mimicking the efficacy of olanzapine while mitigating olanzapine-induced weight gain makes it a promising regimen for improving symptoms and health outcomes in schizophrenic patients.

Project description:Background: Alcohol use disorder (AUD) is a common comorbidity in patients with schizophrenia. Although pharmacological options for the management of each disease exist separately, there is no agent approved for both. Moreover, studies conducted in this patient population, who face practical and social challenges as a consequence of being diagnosed with schizophrenia and comorbid AUD, are limited. Methods: We describe the design of a Phase II, double-blind, randomized trial to evaluate adult outpatients with schizophrenia and comorbid AUD receiving a combination of olanzapine plus samidorphan (OLZ+SAM; ALKS 3831), a novel entity currently under development for the treatment of schizophrenia. The combination drug formulation of OLZ+SAM is intended to provide the antipsychotic efficacy of OLZ while mitigating the weight gain and concomitant metabolic abnormalities commonly associated with OLZ alone. In considering this patient population, the novel primary efficacy endpoint is the time from randomization to the first event of exacerbation of disease symptoms (EEDS) based on the occurrence of any of eight prespecified events related to worsening of disease symptoms and/or AUD, as confirmed by a blinded independent adjudication committee. The rate and number of EEDS, improvement in drinking level, and the safety and tolerability of OLZ in combination with SAM will also be assessed. Discussion: A limited number of studies have been conducted in patients with schizophrenia and AUD, and the need for further research in this difficult-to-study population is well documented. This study is, to our knowledge, the largest and longest trial with a randomized, double-blind, active-controlled design. In addition to providing evidence for the development of OLZ+SAM (ALKS 3831) as a therapeutic option, the study aims to provide insights into the clinical management of subjects with schizophrenia and comorbid AUD. Trial registration: Clinical trials NCT02161718, registered May 2014; EudraCT Number: 2014-001211-39.

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Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia.

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