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Background Combination treatments, targeting multiple disease processes, benefit subjects with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, predicting treatment response and exacerbation risk remain challenging. Objective To identify genetic associations with AECOPD risk and response to combination therapy (fluticasone furoate, umeclidinium bromide and vilanterol). Methods The genetic basis of AECOPD disease was investigated in 19,841 subjects from 23 clinical studies and 2 disease cohorts to identify exacerbation disease targets. AECOPD pharmacogenetic effects were examined in 8,439 moderate to severe COPD patients with exacerbation rate, lung function and quality of life endpoints; results were followed up in an additional 2,201 subjects. Results We did not identify significant associations in the AECOPD disease analysis. In the AECOPD pharmacogenetics analysis, rs56195836 (MAPK8) was significantly associated with moderate to severe exacerbation rate in subjects on fluticasone furoate with baseline blood eosinophils ≥150 cells/μl (P = 1.8 x 10-8). Post-hoc, one variant was associated with on-treatment moderate to severe exacerbation rate stratifying by exacerbation history. AZU1 rs1962343 was significantly associated in subjects with frequent moderate exacerbation history when treated with fluticasone furoate/vilanterol (P = 1.1 x 10-8). Neither of these signals was supported in independent follow-up. Conclusion Common genetic variants do not play major roles in AECOPD disease nor predict response to triple therapy or its components in moderate to very severe COPD.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1β, by central and peripheral immune cells. Il-1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS • Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS-stimulated ATP-induced Il-1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug–receptor interaction. The model has the potential to be used to simulate future trials. AIMS This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.

To The Editor: Inhaled corticosteroids (ICS) are the primary anti-inflammatory therapy for the control and management of asthma, but their effects are characterised by some inter-individual variability that may have a genetic basis1–4. Identification of genetic markers that predict ICS treatment response will facilitate individualised treatment for asthma patients in the future, particularly in those with more severe disease. An association between genetic variation in GLCCI1 and response to ICS therapy in non-Hispanic white asthma subjects was observed by Tantisira et al.5 Genome wide association analysis of 118 trios (one asthmatic child and two parents) from the NHLBI Childhood Asthma Management Program (CAMP) identified 13 single nucleotide polymorphisms (SNPs) with evidence for association with the level of ICS treatment response. These 13 SNPs which included the GLCCI1 promoter polymorphism rs37972, were genotyped and evaluated in four additional independent collections: adult studies SOCS (Salmeterol Or CorticosteroidS) and SLIC (SalmeteroL ± Inhaled CorticosteroidS) (n=264); a second adult study (n=385); LOCCS (Leukotriene modifier Or Corticosteroid or Corticosteroid-Salmeterol) (n=185) and CARE (Childhood Asthma Research and Education) (n=101). In three of the four replicate populations GLCCI1 rs37973, a functional promoter polymorphism5 in complete linkage disequilibrium with rs37972 in white populations, was associated (P

Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism.The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network).A significant association of the coding polymorphism, 601AG, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601AG were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601AG compared to wild-type CYSLTR2.Since 601AG alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.

Background Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability. Objective We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma. Methods Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate–treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV 1 (ΔFEV 1 ) from baseline to 8 to 12 weeks of treatment. Results More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV 1 . No genetic variant met the prespecified threshold for statistical significance. Conclusions This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV 1 ) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma.

Purpose Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. Methods The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90 % confidence intervals were generated. Results The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75 % in DTG AUC(0–τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76 % in DTG AUC(0–τ), Cmax and Cτ, respectively. Conclusions Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients. Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1732-8) contains supplementary material, which is available to authorized users.

This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects.Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated.Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n = 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose.The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.

Genotyping data sets may contain errors that, in some instances, lead to false conclusions. Deviation from Hardy-Weinberg equilibrium (HWE) in random samples may be indicative of problematic assays. This study has analysed 107,000 genotypes generated by TaqMan, RFLP, sequencing or mass spectrometric methods from 443 single-nucleotide polymorphisms (SNPs). These SNPs are distributed both within genes and in intergenic regions. Genotype distributions for 36 out of 313 assays (11.5%) whose minor allele frequencies were >0.05 deviated from HWE (P

Background The efficacy of inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD) varies between patients, which may be partially due to genetic differences. A single-nucleotide polymorphism, rs37972, in the glucocorticoid-induced transcript 1 gene (GLCCI1) has been associated with variations in response (forced expiratory volume in 1 s [FEV1] and residual volume) to fluticasone propionate (Groningen and Leiden Universities Study of Corticosteroids in Obstructive Lung Disease [GLUCOLD] study). The aim of this study was to determine whether variation in the GLCCI1 gene at rs37973 is associated with ICS response in patients with COPD.