Search

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate.

Purpose The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. Methods The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. Results The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. Conclusion This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.

Background Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD. Methods This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C). Results A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg. Conclusions The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD. Trial registration This study was registered with clinicaltrials.gov, NCT03034967.

Danirixin is a selective and reversible CXC chemokine receptor 2 antagonist that may be useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of danirixin after administration of single oral doses of 10, 50, and 100 mg danirixin hydrobromide (HBr) tablets in the fed state (high-fat meal) (part 1) and to evaluate the food effect (low-fat meal) on the pharmacokinetics of danirixin after administration of a single oral dose of 50 mg danirixin HBr tablets (part 2). A total of 34 Japanese healthy elderly male participants were enrolled; 18 participants were included in part 1, and 16 in part 2. The systemic exposure to danirixin (maximum blood concentration [Cmax ] and area under the concentration-time curve [AUC0-t ]) increased in an approximately dose-proportional manner. The exposure to danirixin was lower in the fed state (low-fat meal) than in the fasted state (a 56% and 35% decrease in Cmax and AUC0-t , respectively). This first study of danirixin in Japanese healthy elderly participants showed a favorable safety profile with no drug-related adverse events and no clinically significant concerns in clinical laboratory values, vital signs, ocular examination, or electrocardiograms.

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory–based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model–based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study. Supplementary Information The online version contains supplementary material available at 10.1208/s12248-021-00600-1.

To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution. Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B). TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect. Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution.Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B).TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect.Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.

Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [14C]‐radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2‐period, open‐label study, 6 healthy male subjects received a single IV microtracer 1‐hour infusion of 4 μg [14C]‐batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 μg) followed by oral [14C]‐batefenterol (200 μg) in period 2 after a 14‐day washout. The primary end points included: the area under the concentration‐time curve from time zero to last time of quantifiable concentration (AUC0‐t); maximum observed concentration (Cmax); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0‐t of [14C]‐batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC0‐t ratio indicated that [14C]‐batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [14C]‐batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD). The hydrobromide salt of DNX was identified as having superior biopharmaceutical properties compared to the free base (FB) form in clinical development and the impact of switching to the hydrobromide salt (HBr) was predicted by integrating the nonclinical data in a PBPK model (using GastroPlus™) to enable simulation of clinical drug exposure with FB and HBr salts in the absence and presence of a gastric acid reducing comedication (omeprazole, a proton pump inhibitor (PPI)). Subsequent investigation of DNX pharmacokinetics in a Phase 1 clinical study comparing FB with HBr salt forms confirmed that DNX HBr had reduced the variability of drug exposure and that exposure was not affected by PPI co-administration with DNX HBr. This case study therefore adds to the surprisingly few examples of a more soluble salt of a weak base translating to an improvement in human pharmacokinetics and illustrates a clear clinical benefit of salt selection during drug development.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with approximately 174 million cases worldwide. Electronic questionnaires are increasingly used for collecting patient-reported-outcome (PRO) data about disease symptoms. Our aim was to leverage PRO data, collected to record COPD disease symptoms, in a general modelling framework to enable interpretation of PRO observations in relation to disease progression and potential to predict exacerbations. The data were collected daily over a year, in a prospective, observational study. The e-questionnaire, the EXAcerbations of COPD Tool (EXACT®) included 14 items (i.e. questions) with 4 or 5 ordered categorical response options. An item response theory (IRT) model was used to relate the responses from each item to the underlying latent variable (which we refer to as disease severity), and on each item level, Markov models (MM) with 4 or 5 categories were applied to describe the dependence between consecutive observations. Minimal continuous time MMs were used and parameterised using ordinary differential equations. One hundred twenty-seven COPD patients were included (median age 67 years, 54% male, 39% current smokers), providing approximately 40,000 observations per EXACT® item. The final model suggested that, with time, patients more often reported the same scores as the previous day, i.e. the scores were more stable. The modelled COPD disease severity change over time varied markedly between subjects, but was small in the typical individual. This is the first IRT model with Markovian properties; our analysis proved them necessary for predicting symptom-defined exacerbations. Electronic supplementary material The online version of this article (10.1208/s12248-019-0319-9) contains supplementary material, which is available to authorized users.

To investigate the pharmacokinetics of inhaled batefenterol (BAT) and fluticasone furoate (FF) given alone or in combination via ELLIPTA® dry powder inhaler (DPI-E), and BAT monotherapy via DISKUS® DPI (DPI-D). In this open-label, 6-way crossover study, 48 healthy subjects were randomized to 1 of 6 treatment sequences, comprising 6 single-dose treatment regimens: (1) BAT 1200 μg via DPI-D; (2) BAT 1200 μg via DPI-E without a lactose-filled second strip; (3) BAT 1200 μg via DPI-E with a lactose-filled second strip; (4) BAT/FF 1200/300 μg via DPI-E; (5) FF 300 μg via DPI-E with a lactose-filled second strip; and (6) BAT/FF 900/300 μg via DPI-E. Pharmacokinetic data were analyzed using noncompartmental methods. Plasma BAT area under the curve (AUC) and maximum plasma concentration (Cmax ) were similar for all treatments containing BAT 1200 μg (geometric least-squares means [GLSM] ratio, 0.90-1.06). Plasma FF AUC and Cmax were reduced following BAT/FF 1200/300 μg and 900/300 μg versus FF 300 μg monotherapy (GLSM ratio, 0.62-0.77). BAT 1200 μg administered via DPI-E, alone or in combination with FF, resulted in similar systemic exposure versus BAT administered by DPI-D. FF exposure was reduced when administered in combination with BAT compared with FF alone.

A time-to-event (TTE) model has been developed to characterize a histopathology toxicity that can only be detected at the time of animal sacrifice. The model of choice was a hazard model with a Weibull distribution and dose was a significant covariate. The diagnostic plots showed a satisfactory fit of the data, despite the high degree of left and right censoring. Comparison to a probabilistic logit model shows similar performance in describing the data with a slight underestimation of survival by the Logit model. However, the TTE model was found to be more predictive in extrapolating toxicity risk beyond the observation range of a truncated dataset. The diagnostic and comparison outcomes would suggest using the TTE approach as a first choice for characterizing short and long-term risk from nonclinical toxicity studies. However, further investigations are needed to explore the domain of application of this kind of approach in drug safety assessment.

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and β2‐agonist) administered in combination (BAT/FF) or as monotherapy. In this open‐label, 6‐period, crossover study of 48 subjects, the treatment sequences were (1) single high‐dose BAT/FF 900/300 μg followed by repeated therapeutic doses of BAT/FF 300/100 μg (once daily for 7 days); (2) single high‐dose BAT 900 μg administered concurrently with FF 300 μg; (3) single high‐dose BAT 900 μg followed by repeated therapeutic‐dose BAT 300 μg; (4) single high‐dose FF 300 μg followed by repeated therapeutic‐dose FF 100 μg; (5) single high‐dose FF 300 μg (magnesium stearate); and (6) single high‐dose FF/vilanterol 300/75 μg. Plasma FF area under the plasma drug concentration‐time curve (AUC) was reduced after single high‐dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75‐0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

The no-observed-adverse-effect level (NOAEL) of a drug defined from animal studies is important for inferring a maximal safe dose in human. However, several issues are associated with its concept, determination and application. It is confined to the actual doses used in the study; becomes lower with increasing sample size or dose levels; and reflects the risk level seen in the experiment rather than what may be relevant for human. We explored a pharmacometric approach in an attempt to address these issues. We first used simulation to examine the behaviour of the NOAEL values as determined by current common practice; and then fitted the probability of toxicity as a function of treatment duration and dose to data collected from all applicable toxicology studies of a test compound. Our investigation was in the context of an irreversible toxicity that is detected at the end of the study. Simulations illustrated NOAEL's dependency on experimental factors such as dose and sample size, as well as the underlying uncertainty. Modelling the probability as a continuous function of treatment duration and dose simultaneously to data from multiple studies allowed the estimation of the dose, along with its confidence interval, for a maximal risk level that might be deemed as acceptable for human. The model-based data integration also reconciled between-study inconsistency and explicitly provided maximised estimation confidence. Such alternative NOAEL determination method should be explored for its more efficient data use, more quantifiable insight to toxic doses, and the potential for more relevant animal-to-human translation.

Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders. Substantial variability in the oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes, is largely unaccounted for by clinical variables. A study of 41 patients, 78% (32/41) of whom were non-Hispanic whites, with mild to moderate asthma identified an association of UGT1A1*28 and UGT1A3*2 with the oral clearance of GSK2190915 (P=3.8×10⁻⁴ and 1.2×10⁻⁵, respectively). However, in a subsequent replication study of 403 non-Hispanic white patients with asthma, we failed to observe a statistically significant association between oral clearance of GSK2190915 and either UGT1A1*28 or UGT1A3*2 (P>0.05). Therefore, genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified.

Background: Danirixin (DNX) is a competitive, reversible CXCR2 chemokine receptor antagonist. CXCR2 antagonists inhibit neutrophil migration and activation in the lung in experimental medicine models and several respiratory diseases (COPD, severe asthma and bronchiectasis). Methods: Symptomatic mild-moderate COPD patients at risk for exacerbation (on standard inhaled therapies) were randomized to twice daily, oral DNX (75 mg) or placebo (GSK study 200163, NCT02130193) for 52 weeks. Primary endpoints were respiratory symptoms (Evaluating Respiratory Symptoms in COPD (E-RS:COPD) total and subscale scores) and safety. Secondary endpoints included moderate/severe COPD exacerbations and health status (COPD Assessment Test, CAT). Results: Meaningful improvements in E-RS total score and cough & sputum and breathlessness subscales with DNX occurred 2 months after study start and were maintained through 52 wks (Figure). At 52 wks CAT scores improved -2 points with DNX compared to 0.7 point deterioration with placebo. There was a trend for reduction in exacerbations, including number (39 v 32) and duration (19 v14 days) with DNX. Adverse events were not significantly different for DNX v placebo with no reductions in blood neutrophils. Conclusions: DNX was well-tolerated and associated with improvements in respiratory symptoms and health status. The study was sponsored by GSK.

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.

Aim To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. Method Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. Results There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16–34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nm and 89 nm in the Western European and Japanese studies, respectively. Conclusion GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.

Background: A therapeutic role for histamine H3 receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H1 receptor antagonism. Combined H1/H3 blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage. Methods: Two novel H1/H3 dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20–24 h post-dose. The endpoints included total nasal symptom score and nasal blockage. Results: Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 µg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 µg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort. Conclusions: Combined H1/H3 antagonism did not show differentiation from H1 antagonism in reducing total nasal symptom score or nasal blockage.

Approximately one-third of patients with chronic obstructive pulmonary disease (COPD) have chronic mucus hypersecretion (CMH) [1], often referred to as chronic bronchitis. Despite treatment with inhaled medications and other therapies such as expectorants or methylxanthines, patients with CMH may continue to experience exacerbations, substantial symptom burden and poor health status [1]. CXCR2 antagonists are effective in multiple preclinical and human models of airway inflammation [2–5]. Danirixin is a competitive, reversible oral CXCR2 antagonist that has been well-tolerated in healthy subjects and in patients with influenza [6, 7]. We report the results of a 52-week Phase 2 study conducted in Germany and the USA (GSK protocol 200163; ClinicalTrials.gov identifier [NCT02130193][1]) assessing the effects of danirixin when added to standard-of-care inhaled medications in participants with symptomatic COPD. Participants with an FEV1≥50% of predicted normal and a history of two exacerbations in the prior 12 months, or one exacerbation and elevated plasma fibrinogen ≥3 mg·mL−1, as well as a history of chronic cough and/or mucus hypersecretion on most days for at least the previous 3 months prior screening, were eligible. Full inclusion and exclusion criteria are available online at clinicaltrials.gov. The study was approved by the Western Institutional Review Board (Puyallup, WA, USA) and the Ethikkommission I, Arztekammer Schleswig-Holstein (Bad Segeberg, Germany). Written informed consent was obtained from all participants. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Lazaar is an employee of GlaxoSmithKline and holds stock in the company. Conflict of interest: Dr. Miller reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Yonchuk reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Leidy reports other from Evidera, during the conduct of the study; other from Evidera, outside the submitted work. Conflict of interest: Dr. Ambery reports other from GSK, during the conduct of the study. Conflict of interest: Dr. Bloomer reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Watz reports personal fees from GSK, during the conduct of the study. Conflict of interest: Ms. Tabberer is an employee of and holds stock in GSK. Conflict of interest: Dr. Tal-Singer reports personal fees and other from GSK, during the conduct of the study. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02130193&atom=%2Ferj%2Fearly%2F2018%2F08%2F16%2F13993003.01020-2018.atom

To investigate the pharmacokinetics of inhaled batefenterol (BAT) and fluticasone furoate (FF) given alone or in combination via ELLIPTA® dry powder inhaler (DPI-E), and BAT monotherapy via DISKUS® DPI (DPI-D). In this open-label, 6-way crossover study, 48 healthy subjects were randomized to 1 of 6 treatment sequences, comprising 6 single-dose treatment regimens: (1) BAT 1200 μg via DPI-D; (2) BAT 1200 μg via DPI-E without a lactose-filled second strip; (3) BAT 1200 μg via DPI-E with a lactose-filled second strip; (4) BAT/FF 1200/300 μg via DPI-E; (5) FF 300 μg via DPI-E with a lactose-filled second strip; and (6) BAT/FF 900/300 μg via DPI-E. Pharmacokinetic data were analyzed using noncompartmental methods. Plasma BAT area under the curve (AUC) and maximum plasma concentration (Cmax ) were similar for all treatments containing BAT 1200 μg (geometric least-squares means [GLSM] ratio, 0.90-1.06). Plasma FF AUC and Cmax were reduced following BAT/FF 1200/300 μg and 900/300 μg versus FF 300 μg monotherapy (GLSM ratio, 0.62-0.77). BAT 1200 μg administered via DPI-E, alone or in combination with FF, resulted in similar systemic exposure versus BAT administered by DPI-D. FF exposure was reduced when administered in combination with BAT compared with FF alone.

Modulation of the airways' immune milieu is a key therapeutic goal for remission from respiratory allergies. To explore this hypothesis, GSK2245035, a selective Toll-like receptor 7 (TLR7) agonist with preferential Type-1 interferon (IFN)-stimulating properties, was developed for intranasal application. Doses for clinical assessment were extrapolated from translational biomarker studies in primates. Randomized, double-blind, placebo-controlled trials in healthy volunteers and patients with allergic rhinitis demonstrated that intranasal GSK2245035 doses

Purpose The objective of this study was to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers. Methods Two randomized, double-blind, placebo-controlled studies were conducted. Following optimization of the propranolol dosing regimen (study 1), we conducted a five-period crossover study (study 2) in which subjects received the following treatments: dry powder inhaler (DPI) GSK961081 400 µg + oral placebo, DPI GSK961081 1,200 µg + oral placebo, DPI GSK961081 400 µg + oral propranolol 80 mg, DPI GSK961081 1,200 µg + oral propranolol 80 mg and DPI and oral placebo. GSK961081 (or inhaled placebo) was dosed at 0 h. Propranolol (or oral placebo) was dosed at −8, −2, 4, 10, and 16 h. The primary endpoint for both studies was bronchodilation, measured by specific airway conductance (sGaw), which was assessed at 0, 1, 4, 7, 12, 22, and 24 h in study 2. Tolerability and pharmacokinetics were secondary endpoints. Results Studies 1 and 2 enrolled 18 and 23 subjects, respectively. In study 2, bronchodilation was seen for 24 h following GSK961081 400 and 1,200 μg. In the presence of β2 blockade, GSK961081 1,200 μg demonstrated bronchodilation in the first 4 h after dosing (treatment difference from placebo at 1 h: 1.206; 90 % confidence interval [CI] 1.126–1.292; and at 4 h: 1.124; 90 % CI 1.078–1.173) but not at 7 h onwards. In the presence of β2 blockade, GSK961081 400 μg demonstrated bronchodilation in the first 1 h after dosing (treatment difference from placebo: 1.193; 90 % CI 1.117–1.274), but not at 4 h onwards. Adverse events were reported for 21 (study 1) and 15 subjects (study 2); none were serious, and there were no deaths. Conclusion The duration of bronchodilation as a result of receiving the muscarinic antagonist component alone was shorter than that from the muscarinic antagonist β2 agonist combination. Removing the β2 agonist component may underestimate the contribution of the muscarinic antagonist component to the bronchodilation of the combination.

Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.

Danirixin (GSK1325756) is a small, high-affinity, selective and reversible CXCR2 antagonist in development for treatment of chronic obstructive pulmonary disease. The objective of the study was to evaluate the relative bioavailability, including the inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin during gastric acid suppression in a healthy, elderly population. A single-centre, crossover study in healthy male and female volunteers aged 65–80 years was conducted. Subjects were randomised to receive danirixin 50 mg IR in the fed and fasted states and danirixin 50 mg Bioenhanced Formulation 1 and 2 in the fasted state. All subjects also received omeprazole 20 mg each morning beginning 4 days prior to the first treatment period and continuing through danirixin dosing in the final treatment period. Twenty subjects were randomised and completed the study. Bioenhanced Formulation 2 in the fasted state demonstrated the highest adjusted geometric means for AUC(0–t), AUC(0–inf), AUC(0–24) and Cmax. Danirixin IR demonstrated adjusted means that were higher in the fed state compared with the fasted state. For all formulations tested, there was substantial inter-subject variability (CVb >100 % for all formulations). The overall incidences of adverse events (AEs) were 10 % for danirixin IR (both in the fed and fasted states) and 15–20 % for the bioenhanced formulations. The majority of AEs were mild in intensity. There were no serious AEs. Concomitant use of omeprazole resulted in large inter-subject variability in the exposure to danirixin. Bioenhanced formulation strategies could not overcome the effect of omeprazole on exposure and variability between subjects.

Objective To investigate the pharmacokinetics and pharmacodynamics of inhaled GSK961081 and fluticasone propionate (FP) given alone, concurrently and as a combination blend formulation. Methods The study was double-blind, double-dummy, four-way crossover. Twenty-four healthy volunteers took single doses of the following in randomized order: (1) GSK961081 800 µg; (2) FP 500 µg; (3) GSK961081 800 µg and FP 500 µg as a blend formulation; and (4) GSK961081 800 µg and FP 500 µg concurrently via separate inhalers. The eLung breathing simulator was also used for the in vitro characterization of the formulations. Results There was no pharmacokinetic interaction when GSK961081 and FP were administered concurrently. Mean Cmax and AUC(0−t) of GSK961081 were lower (∼20%) and mean Cmax and AUC(0−t) of FP were higher (two fold) following GSK961081/FP blend formulation compared to concurrent or the individual components alone. There was an increase in the FP in vitro ex-throat dose for the GSK961081/FP blend from the eLung breathing simulator. Serum cortisol suppression was greater with GSK961081/FP blend, with lower (∼10%) cortisol levels than after GSK961081 + FP concurrent or FP alone. Conclusion GSK961081/FP blend formulation was associated with an increase in FP systemic exposure and greater serum cortisol suppression.

Background There are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 μg (MABA 400) or 1200 μg (MABA 1200). Methods This randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 μg at 20 min intervals), IPR (20 μg, 20 μg and 40 μg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV 1 , from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed. Results The additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals. Conclusion The additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy.

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity.There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nM and 89 nM in the Western European and Japanese studies, respectively.GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.

A therapeutic role for histamine H(3) receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H(1) receptor antagonism. Combined H(1)/H(3) blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage.Two novel H(1)/H(3) dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20-24 h post-dose. The endpoints included total nasal symptom score and nasal blockage.Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 μg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 μg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort.Combined H(1)/H(3) antagonism did not show differentiation from H(1) antagonism in reducing total nasal symptom score or nasal blockage.

GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose–response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50–85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10–300 mg), twice-daily inhaled fluticasone propionate 100 μg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose–response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups. Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg. Clinicaltrials.gov: NCT01147744 .

GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 μg) and three twice-daily doses (100, 200, and 400 μg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration-time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD.