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International Journal of Molecular... Sep 2022The preparation of amorphous and co-amorphous systems (CAMs) effectively addresses the solubility and bioavailability issues of poorly water-soluble chemical entities....
The preparation of amorphous and co-amorphous systems (CAMs) effectively addresses the solubility and bioavailability issues of poorly water-soluble chemical entities. However, stress conditions imposed during common pharmaceutical processing (e.g., tableting) may cause the recrystallization of the systems, warranting close stability monitoring throughout production. This work aimed at assessing the water and heat stability of amorphous olanzapine (OLZ) and OLZ-CAMs when subject to wet granulation and pelletization. Starting materials and products were characterized using calorimetry, diffractometry and spectroscopy, and their performance behavior was evaluated by dissolution testing. The results indicated that amorphous OLZ was reconverted back to a crystalline state after exposure to water and heat; conversely, OLZ-CAMs stabilized with saccharin (SAC), a sulfonic acid, did not show any significant loss of the amorphous content, confirming the higher stability of OLZ in the CAM. Besides resistance under the processing conditions of the dosage forms considered, OLZ-CAMs presented a higher solubility and dissolution rate than the respective crystalline counterpart. Furthermore, in situ co-amorphization of OLZ and SAC during granule production with high fractions of water unveils the possibility of reducing production steps and associated costs.
Topics: Crystallization; Drug Stability; Olanzapine; Saccharin; Solubility; Sulfonic Acids; Tablets; Water; X-Ray Diffraction
PubMed: 36142179
DOI: 10.3390/ijms231810234 -
Journal of Child and Adolescent... May 2018To compare the efficacy and safety of olanzapine and risperidone in children and adolescents (aged ≤18 years) with psychosis by conducting a meta-analysis of... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
To compare the efficacy and safety of olanzapine and risperidone in children and adolescents (aged ≤18 years) with psychosis by conducting a meta-analysis of randomized controlled trials (RCTs).
METHODS
Several English and Chinese databases were searched for studies published before February 8th, 2017. Two independent investigators screened the studies according to prespecified criteria and extracted the data. Review Manager 5.3 was used to conduct the data synthesis.
RESULTS
Eight RCTs involving 457 participants (225 participants in the olanzapine group and 232 participants in the risperidone group) were included. No significant differences were observed in the mean scores on the Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale (standard mean difference [SMD] = -0.06, 95% confidence intervals [CI] = [-0.31, 0.19], p = 0.63), the positive symptom scores (SMD = -0.09, 95% CI = [-0.32, 0.15], p = 0.48), or the negative symptom scores (SMD = -0.11 95% CI = [-0.34, 0.13], p = 0.38) between the two groups. Regarding adverse effects, the mean increases in weight (MD = 2.90, 95% CI = [1.41, 4.39], p = 0.0001), body mass index (MD = 0.90, 95% CI = [0.42, 1.38], p = 0.0003), and incidence of hypersomnia (risk ratios [RR] = 1.98, 95% CI = [1.15, 3.43], p = 0.01) were higher in the olanzapine group, while the incidence of insomnia (RR = 0.31, 95% CI = [0.11, 0.85], p = 0.02), prolactin elevation (RR = 0.11, 95% CI = [0.01, 0.85], p = 0.03), myotonia (RR = 0.12, 95% CI = [0.03, 0.49], p = 0.003), tremor (RR = 0.22, 95% CI = [0.08, 0.63], p = 0.005), and akathisia (RR = 0.27, 95% CI = [0.12, 0.57], p = 0.0007) was higher in the risperidone group.
CONCLUSIONS
There is no significant difference in efficacy between olanzapine and risperidone for the treatment of children and adolescents with psychosis, but the side effect profiles of these two medications differ. High-quality RCTs are needed before recommending clinical treatment in children and adolescents.
Topics: Adolescent; Antipsychotic Agents; Child; Humans; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Treatment Outcome
PubMed: 29356569
DOI: 10.1089/cap.2017.0120 -
The Primary Care Companion For CNS... Feb 2021
Topics: Aggression; Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine
PubMed: 34000138
DOI: 10.4088/PCC.20l02719 -
The Cochrane Database of Systematic... Jan 2009Chronic amphetamine users may have experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol,... (Review)
Review
BACKGROUND
Chronic amphetamine users may have experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol, and thioridazine, are effective for the treatment of amphetamine psychosis.
OBJECTIVES
To evaluate risks, benefits, costs of treatments for amphetamine psychosis.
SEARCH STRATEGY
MEDLINE (1966-2007), EMBASE (1980-2007), CINAHL (1982-2007), PsychINFO (1806-2007), CENTRAL (Cochrane Library 2008 issue 1), references of obtained articles.
SELECTION CRITERIA
All randomised controlled and clinical trials (RCTs, CCTs) evaluating treatments (alone or combined) for people with amphetamine psychosis
DATA COLLECTION AND ANALYSIS
Two authors evaluated and extracted the data independently. Dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assess the continuous data.
MAIN RESULTS
The comprehensive searches found one randomised controlled trial of treatment for amphetamine psychosis meeting the criteria for considering studies. The study involved 58 participants and compared the efficacy and tolerability of two antipsychotic drugs, olanzapine (a newer antipsychotic) and haloperidol (a commonly used antipsychotic medication used as a control condition), in treating amphetamine-induced psychosis. The results show that both olanzapine and haloperidol at clinically relevant doses were efficacious in resolving psychotic symptoms, with the olanzapine condition showing significantly greater safety and tolerability than the haloperidol control as measured by frequency and severity of extrapyramidal symptoms.
AUTHORS' CONCLUSIONS
Only one RCT of treatment for amphetamine psychosis has been published. Outcomes from this trial indicate that antipsychotic medications effectively reduce symptoms of amphetamine psychosis, the newer generation and more expensive antipsychotic medication, olanzapine, demonstrates significantly better tolerability than the more affordable and commonly used medication, haloperidol.There are other two studies that did not meet the inclusion criteria for this review. The results of these two studies show that agitation and some psychotic symptoms may be abated within an hour after antipsychotic injection.Whether this limited evidence can be applied for amphetamine psychotic patients is not yet known.The medications that should be further investigate are conventional antipsychotics, newer antipsychotics and benzodiazepines. However, naturalistic studies of amphetamine psychotic symptoms and the prevalence of relapse to psychosis in the presence of amphetamine, are also crucial for advising the development of study designs appropriate for further treatment studies of amphetamine psychosis.
Topics: Amphetamine-Related Disorders; Antipsychotic Agents; Benzodiazepines; Haloperidol; Humans; Olanzapine; Psychoses, Substance-Induced
PubMed: 19160215
DOI: 10.1002/14651858.CD003026.pub3 -
European Journal of Pharmaceutical... Oct 2022Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response...
Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response to olanzapine using a combined approach based on pharmacokinetics, pharmacometabonomics, and genetic polymorphism. The olanzapine pharmacokinetics of 19 healthy volunteers treated with orally disintegrating tablets were determined using high-performance liquid chromatography-tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic analysis using ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. Uridine diphosphate-glucuronosyltransferase (UGT), tyrosine hydroxylase (TH), γ-aminobutyric acid transaminase (GABA-T), and succinic semialdehyde dehydrogenase (SSADH) were identified as key genes. The single nucleotide polymorphism genotypes most related to drug metabolism were investigated by polymerase chain reaction and Sanger sequencing. Forty-one metabolites (p < 0.05) are increased or decreased after treatment with olanzapine. Tryptophan metabolism, norepinephrine metabolism, and γ-aminobutyric acid metabolism were identified as being related to the effects of olanzapine. Subjects carrying rs1641031 AC and CC exhibited a 59.2% increase in the mean peak concentration (C) value and a 25.33% decrease in the mean oral clearance rate (CL/F) value, compared to that in subjects with the GABA-T rs1641031 AA genotype (p < 0.05). Moreover, polymorphism of the GABA-T gene has an impact on the metabolism of 5-hydroxytryptamine. Lysophosphatidylethanolamine (0:0/18:3), lysophosphatidylethanolamine (0:0/22:5), and octadecatrienoic acid distinguish subjects with high and low olanzapine drug oral clearance and are thus identified as biomarkers for predicting its efficacy.
Topics: Chromatography, Liquid; Glucuronosyltransferase; Humans; Olanzapine; Polymorphism, Single Nucleotide; gamma-Aminobutyric Acid
PubMed: 35981664
DOI: 10.1016/j.ejps.2022.106277 -
Annals of Palliative Medicine May 2020
Topics: Antiemetics; Humans; Nausea; Olanzapine; Vomiting
PubMed: 32498523
DOI: 10.21037/apm.2020.04.32 -
Advances in Therapy May 2022Dementia-related psychosis (DRP) is characterized by hallucinations and delusions, which may increase the debilitating effects of underlying dementia. This network... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Dementia-related psychosis (DRP) is characterized by hallucinations and delusions, which may increase the debilitating effects of underlying dementia. This network meta-analysis (NMA) evaluated the comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) commonly used off label to treat DRP.
METHODS
We included 22 eligible studies from a systematic literature review of AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) used off label to treat DRP. Study outcomes were: (1) efficacy-neuropsychiatric inventory-nursing home (NPI-NH psychosis subscale), (2) safety-mortality, cerebrovascular events (CVAEs), and others (somnolence, falls, fractures, injuries, etc.), and (3) acceptability-discontinuations due to all causes, lack of efficacy, and adverse events (AEs). We used random-effects modeling to estimate pooled standardized mean differences (SMDs) for NPI-NH psychosis subscale scores and odds ratios (OR) for other dichotomous outcomes, with their respective 95% confidence intervals (CIs).
RESULTS
Compared with placebo, aripiprazole (SMD - 0.12; 95% CI - 0.31, 0.06), and olanzapine (SMD - 0.17; 95% CI - 0.04; 0.02) demonstrated small, non-significant numerical improvements in NPI-NH psychosis scores (5 studies; n = 1891), while quetiapine (SMD 0.04; 95% CI - 0.23, 0.32) did not improve symptoms. The odds of mortality (15 studies, n = 4989) were higher for aripiprazole (OR 1.58; 95% CI 0.62, 4.04), brexpiprazole (OR 2.22; 95% CI 0.30, 16.56), olanzapine (OR 2.21; 95% CI 0.84, 5.85), quetiapine (OR 1.68; 95% CI 0.70, 4.03), and risperidone (OR 1.63; 95% CI 0.93, 2.85) than for placebo. Risperidone (OR 3.68; 95% CI 1.68, 8.95) and olanzapine (OR 4.47; 95% CI 1.36, 14.69) demonstrated significantly greater odds of CVAEs compared to placebo. Compared with placebo, odds of all-cause discontinuation were significantly lower for aripiprazole (OR 0.71; 95% CI 0.51, 0.98; 20 studies; 5744 patients) and higher for other AAPs. Aripiprazole (OR 0.5; 95% CI 0.31, 0.82) and olanzapine (OR 0.48; 95% CI 0.31, 0.74) had significantly lower odds of discontinuation due to lack of efficacy (OR 12 studies; n = 4382) compared to placebo, while results for quetiapine and risperidone were not significant. Compared with placebo, the odds of discontinuation due to AEs (19 studies, n = 5445) were higher for olanzapine (OR 2.62; 95% CI 1.75, 3.92), brexpiprazole (OR 1.80; 95% CI 0.80, 4.07), quetiapine (OR 1.25; 95% CI 0.82, 1.91), aripiprazole (OR 1.38; 95% CI 0.90, 2.13), and risperidone (OR 1.41; 95% CI 1.02, 1.94).
CONCLUSIONS
Overall results demonstrate that, compared with placebo, quetiapine is not associated with improvement in psychosis in patients with dementia, while olanzapine and aripiprazole have non-significant small numerical improvements. These off-label AAPs (quetiapine, risperidone, olanzapine, aripiprazole, and brexpiprazole) are associated with greater odds of mortality, CVAEs, and discontinuations due to AEs than placebo. These results underscore the ongoing unmet need for newer pharmacological options with a more favorable benefit-risk profile for the treatment of DRP.
Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Dementia; Humans; Network Meta-Analysis; Off-Label Use; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Risperidone; Treatment Outcome
PubMed: 35247186
DOI: 10.1007/s12325-022-02075-8 -
BMC Pharmacology & Toxicology Aug 2013Olanzapine use has been reported during pregnancy and breastfeeding, but there are no controlled clinical trials assessing the safety of olanzapine exposure to infants... (Review)
Review
BACKGROUND
Olanzapine use has been reported during pregnancy and breastfeeding, but there are no controlled clinical trials assessing the safety of olanzapine exposure to infants and fetuses. The purpose of this report was to review and analyze prospective post-marketing cases of pregnancy and breastfeeding with olanzapine, in order to guide clinicians and women on the use of olanzapine therapy during pregnancy and/or breastfeeding.
METHODS
A worldwide safety database maintained by Eli Lilly and Company was searched for all spontaneous-reported data regarding olanzapine use during pregnancy and/or breastfeeding. Cases reported prior to pregnancy outcome were considered to be prospective, and follow-up was pursued after the delivery date to assess outcome.
RESULTS
Outcome data were available for 610 prospectively identified pregnancies during which olanzapine was used. The majority of women had normal births (66%), although premature births were reported in 9.8% and perinatal conditions in 8% of the pregnancies. A total of 102 pregnancies reported olanzapine treatment during breastfeeding. In these infants, the most commonly reported adverse events were somnolence (3.9%), irritability (2%), tremor (2%), and insomnia (2%), although the majority of pregnancies reported no adverse events (82.3%).
CONCLUSIONS
The frequency of fetal outcomes in these prospectively identified pregnancies exposed to olanzapine did not differ from rates of outcomes reported in the general population. These data may be useful to help guide clinicians and women decide to continue, or discontinue, olanzapine therapy during pregnancy and/or breastfeeding, but should be considered within the limitations associated with spontaneously reported data. Women should notify their clinicians if they become pregnant or intend to become pregnant while being treated with olanzapine. Because of limited experience in humans, olanzapine should be used in pregnancy only when potential benefit justifies potential risk to the fetus. Olanzapine should only be considered during breastfeeding when the potential benefit justifies the potential risk to the infant.
Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Benzodiazepines; Breast Feeding; Databases, Factual; Female; Humans; Olanzapine; Pharmacovigilance; Pregnancy; Pregnancy Outcome
PubMed: 23902726
DOI: 10.1186/2050-6511-14-38 -
British Journal of Clinical Pharmacology Feb 2021The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme.
AIMS
The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme.
METHODS
The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults.
RESULTS
Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg.
CONCLUSION
We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.
Topics: Adolescent; Adult; Child; Humans; Infant; Models, Biological; Nonlinear Dynamics; Olanzapine
PubMed: 32497307
DOI: 10.1111/bcp.14414 -
Journal of Psychopharmacology (Oxford,... Oct 2019Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and...
BACKGROUND
Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine.
METHODS
Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels.
RESULTS
Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats.
CONCLUSIONS
Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.
Topics: Adipose Tissue; Animals; Antipsychotic Agents; Drug Combinations; Female; Glucose Metabolism Disorders; Macaca fascicularis; Male; Naltrexone; Narcotic Antagonists; Olanzapine; Rats; Rats, Sprague-Dawley; Sex Factors; Weight Gain
PubMed: 31294646
DOI: 10.1177/0269881119856850