Delving into the Latest Updates on AstraZeneca, Inc. with Synapse

A multicentre, randomised trial in Ontario to evaluate the efficacy of Talking Health Together™ (THT in Practice), a communication education intervention for primary care patients with chronic disease

开始日期2009-03-15

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AstraZeneca, Inc.

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19

项与 AstraZeneca, Inc. 相关的文献（医药）

2024-11-01·Drug Metabolism and Disposition

Assessing Trends in Cytokine–CYP Drug Interactions and Relevance to Drug Dosing

Article

作者: Dai, David ; Phipps, Alex ; Vishwanathan, Karthick ; Sawant-Basak, Aarti ; Olabode, Damilola

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied, in vitro and in clinic. Cytokine-mediated suppression of CYPs or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The FDA recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures (AUC_ss) of CYP-sensitive substrates co-administered with cytokine modulators as reported in the UW DIDB were extracted and examined for each of the CYPs. Co-administration of CYP3A (midazolam/simvastatin), CYP2C19 (omeprazole), or CYP1A2 (caffeine/tizanidine) substrates with anti-IL-6 and with anti-IL-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ -58% to ~35%; no significant trends were observed for CYP2D6 (dextromethorphan) and CYP2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when co-administered with tocilizumab, suggest a ~6-7 fold increase in midazolam clearance suggesting potential implications of cytokine- CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of non-clinical and clinical assessments of cytokine-CYP drug interactions, in drug discovery and development. Significance Statement Significance statement: There has been significant progress in understanding cytokine-mediated drug interactions for CYP-sensitive substrates. This article provides an overview of the progress in this field, including a trend analysis of systemic exposures of CYP-sensitive substrates co-administered with anti-IL-x therapeutics. In addition, the review also provides a perspective of current methods used to assess these drug interactions during drug development, and a focus on individualized medicine, particularly in acute care settings.

2024-04-01·Journal of Pharmaceutical Sciences

Comparison of Commonly Used and New Methods to Determine Small Molecule Non-Specific Binding to Human Liver Microsomes

Article

作者: Whitcher-Johnstone, Andrea ; Wang, Ting ; Scaringella, Young Sun ; Chan, Tom S ; Shao, Juntang ; Keith-Luzzi, Monica ; Taub, Mitchell E

Accurate measurement of non-specific binding of a drug candidate to human liver microsomes (HLM) can be critical for the accurate determination of key enzyme kinetic parameters such as Michaelis-Menton (K_m), reversible inhibition (K_i), or inactivation (K_I) constants. Several methods have been developed to determine non-specific binding of small molecules to HLM, such as rapid equilibrium dialysis (RED), ultrafiltration (UF), HLM bound to magnetizable beads (HLM-beads), ultracentrifugation (UC), the linear extrapolation stability assay (LESA), and the Transil™ system. Despite various differences in methodology between these methods, it is generally presumed that similar free fraction values (f_u,mic) should be generated. To evaluate this hypothesis, a test set of 9 compounds were selected, representing low (high f_u,mic value) and significant (low f_u,mic value) HLM binding, respectively, across HLM concentrations tested in this manuscript. The f_u,mic values were determined using a single compound concentration (1.0 µM) and three HLM concentrations (0.025, 0.50, and 1.0 mg/mL). When the HLM non-specific binding event is not extensive resulting in high f_u,mic values, all methods generated similar f_u,mic values. However, f_u,mic values varied markedly across assay formats when high binding to HLM occurred, where f_u,mic values differed by up to 33-fold depending on the method used. Potential causes for such discrepancies across the various methods employed, practical implications related to conduct the different assays, and implications to clinical drug-drug interaction (DDI) predictions are discussed.

2023-11-07·Circulation

Abstract 12465: The Diagnostic Pathway for Patients With Light Chain (AL) Amyloidosis: Analysis of a Large US Claims Database

作者: Lyons, Genevieve ; Manwani, Richa ; Thompson, Jeffrey ; Maurer, mathew S ; Catini, Julia ; Lousada, Isabelle

Background: Light-chain amyloidosis (AL) is a rare, multisystem disease with a varied presentation, and significant morbidity and mortality. Diagnostic delay can result in poor survival, particularly in patients with cardiac involvement. Aim: To understand the path to diagnosis for patients with AL using US-based claims data. Methods: We conducted a retrospective cohort study of adults (age ≥18 years) with AL using IQVIA PharMetrics Plus data (Jan 1, 2016-Sep 30, 2022). Patients with ≥2 AL diagnosis codes (index is date of second diagnosis; ICD-10: E85.81), ≥24 months’ continuous coverage pre-index, and ≥6 months follow-up were included. Results are reported using descriptive statistics. Results: A total of 1276 patients (58% male, mean age 62 years, 64% treatment naïve) met inclusion criteria at index. In the 2 years pre-index, patients saw the highest number of cardiologists (mean 4.1) compared with hematologist/oncologists (mean 1.8) and nephrologists (mean 1.7). Cardiovascular (CV) symptoms were experienced by 87% of patients within 2 years prior to index; 55% experienced their first CV symptom >1 year prior to index. 71% of patients with CV symptoms had features suggestive of renal involvement, eg, proteinuria. Almost a quarter (23%) of patients had at least 1 emergency room (ER) visit and a third (31%) had at least one inpatient hospitalization (IP) over the 6-month follow-up period. Over half of the ER visits and IP stays were due to CV-related symptoms. Among patients whose diagnosis of AL was delayed (with early onset of CV symptoms >1 year pre-index) compared with those who did not, the crude unadjusted odds of experiencing a CV related ER visit were 53% higher (OR 1.53, 95% CI: 1.09, 2.14; p=0.01). Conclusions: Cardiologists are a key part of the AL diagnostic pathway, as the most visited specialty prior to diagnosis. CV symptoms are the most common experienced by patients with AL and account for the largest proportion of IP stays and ER visits. Patients with delayed AL diagnosis from their first CV symptoms experienced significantly more CV-related ER visits than those without delayed diagnosis. Prompt diagnosis may help prevent a decline and the presence of heart failure symptoms with proteinuria or monoclonal gammopathy should raise suspicion of AL.

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