Model selection and averaging of nonlinear mixed-effect models for robust phase III dose selection

AbstractPopulation model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose –response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model structure uncertainty and model parameter uncertainty using these methodologies, we can make a more robust model based dose selection decision at the end of a phase IIb clinical trial. These methods are investigated using realistic simulation studies based on the study protocol of an actual phase IIb trial for an oral asthma drug candidate (AZD1981). Based on the simulation study, it is demonstrated that a bootstrap model selection method properly av oids model selection bias and in most cases increases the accuracy of the end of phase IIb decision. Thus, we recommend using this bootstrap model selection method when conducting population model-based decision-making at the end of phase IIb clinical trials.
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

Related Links:

Publication date: Available online 18 January 2020Source: Pulmonary Pharmacology &TherapeuticsAuthor(s): Linda Marie Schellenberg, Jana Bonicelli, Ina Hochheim, Ralf Regenthal, Getu AbrahamAbstractThe β-adrenergic receptor (β-AR) plays an important role in regulating a variety of cell and organ functions in different animal species and is an important target in asthma pathogenesis and therapy. The β-AR expression and function in equine bronchial epithelial cells (EBEC) were not known but innervation and significant decrease in receptor level were reported in the equine bronchial tissues from asthmatic ho...
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research
Source: Human Vaccines and Immunotherapeutics - Category: Allergy & Immunology Authors: Source Type: research
This study describes the long-term comorbidity profile and treatment burden among people with HIV-1 infection.Methods: This retrospective study included Medicaid claims data from patients with ≥1 antiretroviral (ARV) claim between 2016 and 2017 (most recent claim defined the index date), ≥1 HIV diagnosis within 1 year before index, age ≥18 years at first HIV diagnosis and
Source: Current Medical Research and Opinion - Category: Research Tags: Curr Med Res Opin Source Type: research
Khreis Air pollution is associated with premature mortality and a wide spectrum of diseases. Traffic-related air pollution (TRAP) is one of the most concerning sources of air pollution for human exposure and health. Until TRAP levels can be significantly reduced on a global scale, there is a need for effective shorter-term strategies to prevent the adverse health effects of TRAP. A growing number of studies suggest that increasing antioxidant intake, through diet or supplementation, may reduce this burden of disease. In this paper, we conducted a non-systematic literature review to assess the available evidence on ant...
Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Review Source Type: research
Authors: Kalmarzi RN, Ahmadi S, Rahehagh R, Fathallahpour A, Khalafi B, Kashefi H, Roshani D, Zaryan RN, Mohamadi S, Kooti W Abstract BACKGROUND: The extensive impacts of vitamin D on the immune system has gathered the attention of scholars in last years. In this regard, studies about vitamin D and incidence of asthma have showed various results. The aim of this study was to evaluate the effect of vitamin D supplements on clinical outcomes in asthmatic children with vitamin D insufficiency. MATERIALS &METHODS: This before-after interventional study was conducted on all asthmatic children who attended the Be...
Source: Endocrine, Metabolic and Immune Disorders Drug Targets - Category: Drugs & Pharmacology Tags: Endocr Metab Immune Disord Drug Targets Source Type: research
This study investigated the protective effects of ascorbic acid in combination with calcitriol on airway remodelling in ovalbumin (OVA)-induced chronic asthma.Materials and methods: BALB/c mice were assigned into seven groups: (1) Control; (2) Asthma; (3) Ineffective C (orally 39 mg/kg ascorbic acid); (4) Ineffective D (intraperitoneally 1.5 μg/kg calcitriol); (5) Effective C (orally 130 mg/kg ascorbic acid); (6) Effective D (intraperitoneally 5 μg/kg calcitriol); (7) Combination (orally 39 mg/kg ascorbic acid + intraperitoneally 1.5 μg/kg calcitriol). All an...
Source: Pharmaceutical Biology - Category: Drugs & Pharmacology Tags: Pharm Biol Source Type: research
Publication date: Available online 16 January 2020Source: Journal of Molecular Graphics and ModellingAuthor(s): Yonghui Lv, Yu Wang, Xin Zheng, Guizhao LiangAbstractVEGFR2, vascular endothelial growth factor receptor 2, plays an important role in anti-angiogenesis and is an effective target for inhibiting tumor cell proliferation and metastasis. Many small molecule inhibitors have so far exhibited fine therapeutic effects but do not rule out some adverse reactions. From the perspective of the new use of old drugs, we use a combination of two different docking methods, molecular dynamics simulations and quantum-chemical cal...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research
Publication date: Available online 17 January 2020Source: Revista Clínica Española (English Edition)Author(s): E. Martínez-Moragón, J. Delgado, S. Mogrovejo, T. Fernández-Sánchez, On behalf of the grupo de investigación STEP, Jesús Jiménez López, Miguel Ángel Moscardó Orenes, Patricia Prieto Montaño, Miguel Torrecillas Toro, Begoña Cueva Oliver, Ángel Ferrer Torres, Purificación González Delgado, Teodorikez Wilfox Jiménez Rodríguez, Brian Vila Auli, Juan José Zapata Yebenes, Marí...
Source: Revista Clinica Espanola - Category: Internal Medicine Source Type: research
BPA exposure may activate an immune system response linked to asthma that is passed down through generations, according to a study published in the journal ofProteome Research.Science Daily
Source: Society for Endocrinology - Category: Endocrinology Source Type: news
The Pharmacogenomics Journal, Published online: 17 January 2020; doi:10.1038/s41397-019-0140-yPharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation
Source: The Pharmacogenomics Journal - Category: Drugs & Pharmacology Authors: Source Type: research
More News: Asthma | Clinical Trials | Drugs & Pharmacology | Study