| Reference | 1. J Pharmacol Exp Ther. 2018 Jun;365(3):567-572. doi: 10.1124/jpet.117.246132. Epub 2018 Mar 16.<br />
AZD7624, an Inhaled p38 Inhibitor, Demonstrates Local Lung Inhibition of LPS-Induced TNFα with Minimal Systemic Exposure.<br />
Pehrson R(1), Hegelund-Myrbäck T(2), Cunoosamy D(2), Asimus S(2), Jansson P(2), Patel N(2), Borde A(2), Lundin S(2).<br />
Author information:<br />
(1)AstraZeneca, Mölndal, Sweden [email protected]. (2)AstraZeneca, Mölndal, Sweden.<br />
Inhaled drugs generally aim to drive a local pharmacological effect in lung, at the same time minimizing systemic exposure, in order to obtain efficacy in lung disease without unwanted systemic effects. Here, we demonstrate that inhaled delivery of a p38 inhibitor (AZD7624) can provide superior pharmacokinetic exposure and superior pharmacodynamic lung effects. In rats, inhaled AZD7624 had a five times higher dose-adjusted lung exposure compared with intravenous dosing. In healthy volunteers, lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) in sputum has been shown to be significantly reduced (85%) by means of inhaled AZD7624. Here, we demonstrate that this effect is associated with a mean unbound plasma concentration, gained from in vitro and ex vivo LPS-challenge protocols, significantly below potencies obtained for AZD7624, suggesting that lung exposure is probably much higher than systemic exposure. This assessment was made for the unbound potency (pIC50u), e.g., the potency remaining after adjustment for plasma protein binding and blood plasma ratio. Hence, the unbound potency of AZD7624 to inhibit LPS-induced TNFα in human mononuclear cells, in whole blood as well as in alveolar macrophages in vitro, was 8.4, 8.7 (full inhibition), and 9.0 (partial inhibition), respectively. The pIC50u in whole blood ex vivo was 8.8, showing good in vitro/in vivo potency correlations. Thus, a mean unbound AZD7624 plasma concentration of 0.3 nmol/l, which was associated with a decrease in LPS-induced sputum TNFα by 85%, is much lower than the pIC50u. This demonstrates that AZD7624 can achieve significant local lung pharmacodynamic effects with concomitant sub-pharmacological systemic exposure.<br />
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2. Int J Chron Obstruct Pulmon Dis. 2018 Apr 19;13:1279-1288. doi: 10.2147/COPD.S159936. eCollection 2018.<br />
Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells.<br />
Higham A(1)(2), Karur P(1)(2), Jackson N(2), Cunoosamy DM(3), Jansson P(3), Singh D(1)(2).<br />
Author information:<br />
(1)Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK. (2)Medicines Evaluation Unit, The University Hospital of South Manchester, Manchester, UK. (3)RIA IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.<br />
Background: The effects of anti-inflammatory drugs in COPD patients may vary between different cell types. The aim of the current study was to assess the anti-inflammatory effects of the corticosteroid budesonide and a p38 MAPK inhibitor (AZD7624) on different cell types obtained from COPD patients and healthy controls.<br />
Methods: Eight healthy smokers, 16 COPD infrequent exacerbators, and 16 frequent COPD exacerbators (≥2 exacerbations in the last year) were recruited for bronchoscopy and blood sampling. The anti-inflammatory effects of budesonide and AZD7624 were assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages and peripheral blood mononuclear cells and polyinosinic:polycytidylic acid-stimulated bronchial epithelial cells. Results: The anti-inflammatory effects of budesonide varied greatly within a patient according to the cell type studied. Bronchial epithelial cells showed the lowest sensitivity to budesonide, while peripheral blood mononuclear cells showed the greatest sensitivity. AZD7624 had a greater effect than budesonide on cytokine production from bronchial epithelial cells. Exacerbation frequency did not influence corticosteroid sensitivity.<br />
Conclusion: We observed variable corticosteroid and p38 MAPK inhibitor anti-inflammatory responses within the same individual depending on the cell type studied. These findings support the use of multiple anti-inflammatory strategies in COPD patients due to differences between cell types.<br />
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3. Int J Chron Obstruct Pulmon Dis. 2018 Mar 27;13:1009-1019. doi: 10.2147/COPD.S150576. eCollection 2018.<br />
The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial.<br />
Patel NR(1)(2), Cunoosamy DM(1), Fagerås M(1), Taib Z(1), Asimus S(1), Hegelund-Myrbäck T(1), Lundin S(1), Pardali K(1), Kurian N(1), Ersdal E(1), Kristensson C(1), Korsback K(1), Palmér R(1), Brown MN(3), Greenaway S(4), Siew L(4), Clarke GW(4)(5), Rennard SI(6)(7), Make BJ(8), Wise RA(9), Jansson P(1).<br />
Author information:<br />
(1)Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden. (2)Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA. (3)Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA. (4)Quintiles Drug Research Unit at Guy's Hospital, London. (5)Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK. (6)Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA. (7)Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK. (8)Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO. (9)Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.<br />
Background: 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.<br />
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.<br />
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.<br />
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.<br />
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