Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

Naimish R Patel,1,2 Danen M Cunoosamy,1 Malin Fagerås,1 Ziad Taib,1 Sara Asimus,1 Tove Hegelund-Myrbäck,1 Sofia Lundin,1 Katerina Pardali,1 Nisha Kurian,1 Eva Ersdal,1 Cecilia Kristensson,1 Katarina Korsback,1 Robert Palmér,1 Mary N Brown,3 Steven Greenaway,4 Leonard Siew,4 Graham W Clarke,4,5 Stephen I Rennard,6,7 Barry J Make,8 Robert A Wise,9 Paul Jansson11Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA, 3Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA; 4Quintiles Drug Research Unit at Guy’s Hospital, London, 5Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK; 6Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA; 7Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK; 8Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, 9Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USABackground: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18–55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40–85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.Conclusion: Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD. Keywords: COPD, inflammation, p38 mitogen-activated protein kinas

Pressure injury prevalence and predictors among older adults in the first 36-hours of hospitalisation

To describe the prevalence and predictors of pressure injuries among older adults with limited mobility, within the first 36-hours of their hospital admission in Australia. Pressure injuries are significant health, safety and quality of care issues for patients and healthcare organisations. The early implementation of the recommended pressure injury prevention international clinical practice guidelines is a way to reduce hospital-acquired pressure injuries. There is a paucity of evidence on the number of older persons who are admitted hospital with a pre-existing pressure injury. Prospective correlational study conducted in eight tertiary referral hospitals across Australia. Our sample comprised of 1047 participants aged ≥65 years with limited mobility, drawn from a larger Australian pragmatic cluster randomised trial. Using the STROBE statement, observational data were collected on participants' age, gender, presence of a pressure injury, Body Mass Index score, number of comorbidities and place of residence. These variables were analysed as potential predictors for pressure injuries within the first 36-hours of hospitalisation. From our sample, 113/1047 (10.8%) participants were observed to have a pressure injury within the first 36-hours of hospital admission. Age, multiple comorbidities, and living in an aged care facility predicted the prevalence of pressure injury among older people within the first 36-hours of hospitalisation. Our findings confirm that older adults, those with multiple comorbidities, and individuals living in aged care facilities are more likely to come to hospital with a pre-existing pressure injury or develop one soon after admission. This article is protected by copyright. All rights reserved