Adasuve (staccato loxapine) / AOP Orphan Pharma, Teva, Ferrer International, Galen, Medivir - LARVOL DELTA

Population Pharmacokinetics of Osimertinib in Patients With Non-Small Cell Lung Cancer. (PubMed, Pharmacol Res Perspect) - "Updated popPK analyses were based on patients from AURA (n = 599), AURA2 (n = 210), AURA3 (n = 277), and FLAURA (n = 278) using a linear one-compartmental disposition model for osimertinib and its metabolite, AZ5104, with first-order oral absorption. Visual predictive checks showed that the final model validated osimertinib steady-state PK for adjuvant treatment. PopPK modeling indicated that osimertinib dose adjustment is not required for patients' age, sex, body weight, race, smoking status, or line of therapy, confirming that a fixed 80 mg once-daily dose is optimal for osimertinib."

Journal • PK/PD data • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Psychiatry • Solid Tumor

A 2024 Update on US FDA Implementation of Partial Area Under the Curve Into Bioavailability and Bioequivalence Assessments. (PubMed, Clin Pharmacol Ther) - "Notable regulatory examples of pAUC applications discussed include loxapine inhalation powder, leuprolide long-acting injectables (LAIs), and goserelin LAIs. This paper discusses recent applications of pAUC in the United States, highlights key examples of pAUC recommendations for regulatory applications, and provides insights about areas for global harmonization of pAUC recommendations."

Journal • Review

Development and validation of an LC-MS/MS method for quantification of Osimertinib and its two metabolites AZ7550 and AZ5104 in human plasma including long-time storage. (PubMed, J Pharm Biomed Anal) - "Stability was examined under different conditions, and the analytes were found to be stable for more than 3 years at -80°C (< 15 % decline). Finally, the analytical method was successfully applied in a clinical setting on plasma samples from 30 patients with non-small cell lung cancer in treatment with osimertinib, demonstrating its suitability for use in clinical studies and its potential for therapeutic drug monitoring."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Efficacy and Adverse Events of Osimertinib Correlate With Blood Concentration of Osimertinib and Its Active Metabolites, AZ5104 and AZ7550 (ATS 2024) - "9 months in the AURA study (epidermal growth factor receptor [EGFR] T790M-positive non-small cell lung cancer [NSCLC] patients treated with osimertinib or platinum-pemetrexed) and 19. 8 months in the FLAURA study (previously untreated, EGFR mutation-positive advanced NSCLC patients who received either osimertinib or a standard EGFR-tyrosine kinase inhibitor [TKI], such as gefitinib or erlotinib), significantly longer than that of first-generation EGFR-TKIs...[Conclusion] Blood osimertinib concentration may influence PFS. In addition, the active metabolite AZ7550 may correlate with adverse effects, particularly hematologic toxicity."

Adverse events • Clinical • Anemia • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer

Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "All four popPK models can be used to individually predict osimertinib concentrations in patients with low osimertinib exposure. For population predictions, all four popPK models performed poorly in patients with low osimertinib exposure. A novel popPK model with good predictive performance should be developed for patients with low osimertinib exposure. Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Validation of Liquid Chromatography Coupled with Tandem Mass Spectrometry for the Determination of 12 Tyrosine Kinase Inhibitors (TKIs) and Their Application to Therapeutic Drug Monitoring in Adult and Pediatric Populations. (PubMed, Pharmaceutics) - "A multitarget LC-MS/MS method was developed and validated for the determination of alectinib, alectinib-M4, binimetinib, cobimetinib, crizotinib, dabrafenib, encorafenib, imatinib, lorlatinib, osimertinib, AZ5104, and trametinib. This method has been successfully applied to the therapeutic drug monitoring (TDM) of adults with melanoma and lung cancer, as well as children with histiocytosis, to improve the pharmacokinetic data for these drugs, with the aim of enhancing the therapeutic management and follow-up of patients. Blood concentrations of trametinib and binimetinib were different in the two groups, highlighting the age-related inter-individual variability of these molecules and the need for TDM."

Journal • Langerhans Cell Histiocytosis • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Pediatrics • Solid Tumor

Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder. (PubMed, Prim Care Companion CNS Disord) - "However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film...Prim Care Companion CNS Disord 2024;26(1):23nr03596. Author affiliations are listed at the end of this article."

Journal • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

A Validated Assay to Quantify Osimertinib and Its Metabolites, AZ5104 and AZ7550, from Microsampled Dried Blood Spots and Plasma. (PubMed, Ther Drug Monit) - "The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A Prospective Cohort Study Assessing the Relationship between Plasma Levels of Osimertinib and Treatment Efficacy and Safety. (PubMed, Biomedicines) - "The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted."

Journal • Anorexia • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia • EGFR

Improving the pharmacotherapeutic treatment of agitation associated with bipolar disorder. (PubMed, Expert Opin Pharmacother) - "A goal is to treat mild agitation before it evolves into severe agitation, encouraging noninvasive pharmacologic treatment options. Inhaled loxapine and sublingual dexmedetomidine are newer options with rapid onset-of-actions and may be preferable for patients willing to cooperate with treatment."

Journal • Review • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry

Synthesis and preclinical evaluation of two osimertinib isotopologues labeled with carbon-11 as PET tracers targeting the tyrosine kinase domain of the epidermal growth factor receptor. (PubMed, Nucl Med Biol) - "Osimertinib was successfully labeled at two positions with carbon-11, yielding two EGFR PET tracers, [methylindole-C]osimertinib and [dimethylamine-C]osimertinib. The preclinical evaluation demonstrated uptake and retention in three NSCLC xenografts; A549, HCC827, and H1975. The highest uptake was observed in the primary Del19 EGFR mutated HCC827. The ability of [methylindole-C]osimertinib to distinguish between the T790M resistance mutated H1975 xenografts and the wild-type EGFR expressing A549 could not be confirmed in the ex vivo study."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

The metabolism and pharmacokinetic study of deuterated osimertinib. (PubMed, Biopharm Drug Dispos) - "Among the metabolites produced by the osimertinib, AZ5104 and AZ7550 which are demethylated are most vital. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C ) compared with the osimertinib in rats and human body."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study. (PubMed, Invest New Drugs) - "Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management."

Adverse events • Biomarker • Journal • Metastases • Observational data • PK/PD data • Anorexia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • EGFR

Dexmedetomidine sublingual film (Igalmi) for acute agitation. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

Novel Antipsychotics and Risk of Drug-Induced Movement Disorders and Tardive Syndromes (MDS Congress 2022) - "Within the last ten years, six novel antipsychotics (brexpiprazole, cariprazine, lurasidone, lumateperone, pimavanserin, olanzapine-samidorphan) and five novel formulations (long-acting injectable [LAI] risperidone, LAI aripiprazole, LAI paliperidone, transdermal asenapine, and inhaled loxapine) of antipsychotics have received FDA approval [2]. Several novel APs, such as lumateperone and pimavanserin, show minimal risk of DIMDs and tardive syndromes. Compared to oral paliperidone, the LAI may decrease risk of DIMDs while LAI risperidone and aripiprazole have equal risk compared to oral formulations. Furthermore, new experimental drug targets that do not use dopamine receptor blockade show promise in reducing incidence of DIMDs."

CNS Disorders • Psychiatry

Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial. (PubMed, Lung Cancer) - P1 | "Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable."

Journal • PK/PD data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Inhaled Loxapine as a Rapid Treatment for Agitation in Patients with Personality Disorder: A Prospective Study on the Effects of Time. (PubMed, Clin Psychopharmacol Neurosci) - "No additional treatments were needed to improve agitation during the follow-up time. Results suggest that IL could be a safe and effective option to manage agitation in PD."

Journal • Borderline Personality Disorder • CNS Disorders • Mood Disorders • Personality Disorder • Psychomotor Agitation

A phase II study of osimertinib for radiotherapy-naïve CNS metastasis from non-small cell lung cancer: Results for the T790M cohort of the OCEAN study (LOGIK1603/WJOG9116L). (PubMed, J Thorac Oncol) - "This study assessed the efficacy of osimertinib against radiotherapy-naïve CNS metastasis from T790M-positive NSCLC. The primary endpoint was met, and the results demonstrated the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • EGFR

Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The Influence of CYP3A4 Genetic Polymorphism and Proton Pump Inhibitors on Osimertinib Metabolism. (PubMed, Front Pharmacol) - "Sixteen of them inhibited the production of AZ5104 to 20% or less, especially proton pump inhibitors, among which the IC of rabeprazole was 6.49 ± 1.17 μM in RLM and 20.39 ± 2.32 μM in human liver microsome (HLM), with both following competitive and non-competitive mixed mechanism. In an in vivo study, Sprague-Dawley (SD) rats were randomly divided into groups, with six animals per group, receiving osimertinib with or without rabeprazole, omeprazole, and lansoprazole. We found that the AUC, AUC, and C of osimertinib decreased significantly after co-administration with rabeprazole orally, but they increased remarkably when osimertinib was administered through intraperitoneal injection. Taken together, our data demonstrate that the genetic polymorphism and proton pump inhibitors remarkably influence the disposition of osimertinib, thereby providing basic data for the precise application of osimertinib."

Journal • CYP3A4

New Antipsychotic Medications in the Last Decade. (PubMed, Curr Psychiatry Rep) - "We identified 11 significant developments: the introduction of new antipsychotics cariprazine, brexpiprazole, lumateperone, and pimavanserin; introduction of new delivery subcutaneous long-acting risperidone, aripiprazole lauroxil, transdermal asenapine, and inhaled loxapine; and the introduction of new approaches such as olanzapine/samidorphan for olanzapine-associated weight gain, examination of the TAAR1 agonist SEP 363,856 as a test of concept, and the combination of Xanomeline/Trospium, an M and M muscarinic receptor agonist in conjunction with a peripheral anticholinergic. Last decade has seen a tremendous development in second-generation antipsychotics which provides unprecedented treatment options for clinicians in treating psychosis."

Journal • Review • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

[VIRTUAL] A Prospective Observational Study of Osimertinib Using Plasma Concentrations in NSCLC With Acquired EGFR T790M Mutation (IASLC-WCLC 2021) - "Plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment, and at the onset of AE that required suspension or discontinuation of treatment. An appropriate plasma level of osimertinib may avoid some adverse events and may induce long PFS. Further analysis is required."

Clinical • Observational data • Anemia • Anorexia • Gastrointestinal Disorder • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • Thrombocytopenia • EGFR

Inhaled loxapine for acute agitation in a psychiatric emergency service. (PubMed, Ann Clin Psychiatry) - "The rapid absorption of inhaled loxapine is associated with a 6-fold faster and more robust symptom control."

Journal • Psychiatry

Discovery of Dosimertinib, a Highly Potent, Selective, and Orally Efficacious Deuterated EGFR Targeting Clinical Candidate for the Treatment of Non-Small-Cell Lung Cancer. (PubMed, J Med Chem) - "However, AZ5104, a primary toxic metabolite of osimertinib, has caused unwanted toxicities. These preclinical data support further clinical development of dosimertinib for the treatment of NSCLC. Dosimertinib has received official approval in China to initiate the phase I clinical trial (registration numbers: CXHL2000060 and CXHL2000061)."

Clinical • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

Rates of adverse and serious adverse events in children with cystic fibrosis. (PubMed, J Cyst Fibros) - "AEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates."

Adverse events • Clinical • Journal • Serious adverse event • Cystic Fibrosis • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases