Rashmi Mehta

Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients

BACKGROUNDnThis study evaluated the dose-response of the new long-acting muscarinic antagonist umeclidinium (GSK573719) in patients with COPD.nnnMETHODSnThis randomized, double-blind, placebo-controlled, parallel-group study evaluated three once-daily doses of umeclidinium (125, 250 and 500 μg) for 28 days in 285 patients with COPD having FEV(1) of 35-70% predicted (mean (SD) age=61.4 (8.41); mean (SD) post-bronchodilator FEV(1)=1.577 (0.450)). The primary endpoint was morning trough FEV(1) at Day 29. Secondary endpoints included 0-6h weighted mean FEV(1) and serial FEV(1) measured over 6h post-dose and at trough. Safety and pharmacokinetics were also assessed.nnnRESULTSnAll doses of umeclidinium significantly increased trough FEV(1) over placebo from 150 to 168 mL (p<0.001), 0-6h weighted mean FEV(1) from 113 to 211 mL (p<0.001), and serial FEV(1) at each point in time over 24h. Reductions in salbutamol use and improvements in FVC were noted for all doses. Umeclidinium was well tolerated with no apparent treatment-related changes in vital signs.nnnCONCLUSIONnOnce-daily umeclidinium provides clinically significant, sustained improvement in lung function and is well tolerated.

Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study.

Background The combination of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a selective long-acting β2 agonist, is in development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacokinetics, safety and tolerability, and pharmacodynamics of once-daily, inhaled UMEC and UMEC/VI when co-administered with oral verapamil, a moderate P-glycoprotein transporter and moderate cytochrome P450 3A4 (CYP3A4) inhibitor frequently used by patients with COPD and cardiovascular comorbidities. Methods Subjects were randomized to one of two 13-day treatment regimens: UMEC 500 μg or UMEC 500 μg/VI 25 μg. All subjects received a single tablet containing 240 mg verapamil on each of days 9–13. Results Repeat doses of UMEC and UMEC/VI in combination with and without verapamil were safe and well tolerated. There was no increase in systemic exposure of UMEC when administered in combination with VI compared to UMEC alone. UMEC maximum concentration was similar with or without verapamil; a moderate increase in UMEC area under the curve (approximately 1.4-fold) was observed with verapamil. Verapamil did not increase systemic exposure to VI following administration of the UMEC/VI combination. Conclusion Administration of UMEC and UMEC/VI combination was well tolerated and did not show clinically relevant increases in systemic exposure for either drug. The UMEC/VI combination is unlikely to have a clinically meaningful drug–drug interaction with moderate P-glycoprotein transporter and CYP3A4 inhibitor drugs.

Population Pharmacokinetics of Inhaled Umeclidinium and Vilanterol in Patients with Chronic Obstructive Pulmonary Disease

Background and objectivesA fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure.MethodsPlasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM® software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model.ResultsFor the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V2/F).The population parameter estimates namely CL/F and V2/F for umeclidinium were 218xa0L/h and 1,160xa0L and 40.9xa0L/h and 268xa0L for vilanterol.For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10xa0% increase in bodyweight will result in a 2xa0% increase in CL/F for umeclidinium and vilanterol and 6xa0% increase in umeclidinium V2/F. A 10xa0% increase in age will provide a 7 and 4xa0% decrease in umeclidinium and vilanterol CL/F, respectively. A 10xa0% decrease in CLCR will result in a 3xa0% decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination.ConclusionsThere were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Inhaled Doses of Umeclidinium in Healthy Subjects: Two Randomized Studies

BackgroundChronic obstructive pulmonary disease (COPD) has a significant negative impact on quality of life and increases the risk of premature death. Umeclidinium is a long-acting muscarinic receptor antagonist in development for the treatment of COPD with the aim to broaden treatment options for clinicians and patients by providing improved symptom control.ObjectiveTo characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects.Study DesignTwo randomized, placebo-controlled, ascending-dose studies were conducted in healthy ipratropium bromide-responsive subjects. In the single-dose study, subjects (nxa0=xa020) received umeclidinium (10–350xa0μg), tiotropium bromide 18xa0μg and placebo in a crossover dosing schedule. In this study, lung function was assessed for 24xa0h by measuring specific airways conductance (sGaw) and forced expiratory volume in 1xa0s (FEV1). In the repeat-dose study, subjects (nxa0=xa036) received umeclidinium (250–1,000xa0μg) and placebo for 14xa0days in a parallel-group schedule.ResultsAdverse events (AEs) were reported in five subjects (single-dose study) and 23xa0subjects (repeat-dose study); none were serious. In both studies, no abnormalities in 12-lead electrocardiogram parameters, 24-h Holter monitoring or lead II monitoring were reported as AEs. Umeclidinium was rapidly absorbed following single-dose administration [time to reach the maximum plasma concentration (tmax) 5–15xa0min] and repeat-dose administration (tmax 5–7xa0min). Following repeat dosing, the geometric mean plasma elimination half-life was approximately 27xa0h and statistically significant accumulation was observed for the area under the plasma concentration–time curve, maximum plasma concentration and cumulative amount of unchanged drug excreted into the urine at 24xa0h (range 1.5- to 4.5-fold). Umeclidinium at doses of 100xa0μg and above, and tiotropium bromide demonstrated statistically significant bronchodilatory effects relative to placebo at 12xa0h post-dosing, which lasted up to 24xa0h for umeclidinium 350xa0μg and for tiotropium bromide. Relative to placebo, these increases in sGaw were 24–34xa0% at 12xa0h post-dose and 13xa0% at 24xa0h post-dose. Increases in FEV1 achieved statistical significance at 12 and 24xa0h for umeclidinium 100xa0μg and 350xa0μg compared with placebo.ConclusionUmeclidinium was well tolerated and demonstrated bronchodilatory effects in healthy subjects for up to 24xa0h. These bronchodilatory effects can be potentially clinically important in patients with airway obstruction such as COPD. The data obtained have informed dose selection for subsequent trials in subjects with COPD.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

Objective: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. Methods: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPTA® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 μg, FF/UMEC 400/500 μg, UMEC/VI 500/100 μg, or FF/VI 400/100 μg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 μg or 400/250/100 μg, FF/VI 400/100 μg, or UMEC/VI 250/100 μg. PK and PD parameters and safety were assessed. Results: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. Conclusions: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

Safety and efficacy of dual therapy with GSK233705 and salmeterol versus monotherapy with salmeterol, tiotropium, or placebo in a crossover pilot study in partially reversible COPD patients

Background GSK233705 is an inhaled, long-acting muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This study was performed to see if the addition of GSK233705 to salmeterol would provide greater bronchodilation than salmeterol or tiotropium alone in COPD. Methods In an incomplete-block, three-period, crossover design, dually responsive patients received three of the following five treatments: GSK233705 20 μg plus salmeterol 50 μg twice-daily; GSK233705 50 μg plus salmeterol 50 μg twice-daily; salmeterol 50 μg or placebo, each twice-daily; and tiotropium 18 μg or placebo once-daily for 7 days. Each treatment period was separated by a 14-day washout. The primary efficacy endpoint was morning (trough) forced expiratory volume in 1 second (FEV1) on Day 8, following 7 days of treatment. Secondary endpoints included pulmonary function, plethysmography, pharmacokinetics of GSK233705 and salmeterol, adverse events (AEs), electrocardiograms (ECGs), vital signs, and laboratory parameters. Results A total of 47 patients were randomized. The mean % predicted normal postbronchodilator FEV1 was 55% at screening. Compared with placebo (n = 24), the adjusted mean change from baseline in trough FEV1 on Day 8 was 215 mL higher with GSK233705 20 μg + salmeterol (n = 23) and 203 mL higher with GSK233705 50 μg + salmeterol (n = 27), whereas with salmeterol (n = 27) and tiotropium (n = 28) the changes were 101 mL and 118 mL higher, respectively. The primary efficacy results were supported by the results from the other secondary lung function assessments. AEs were reported by similar proportions of patients across the treatment groups, with headache the most frequently reported treatment-related AE reported by one subject receiving each of GSK233705 20 μg + salmeterol, tiotropium, and placebo. No significant differences were seen in vital signs, ECGs, or laboratory parameters between the groups. Conclusion The addition of GSK233705 to salmeterol in partially reversible COPD patients resulted in greater bronchodilation than salmeterol or tiotropium alone and was well tolerated.

Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Inhaled Once-Daily Umeclidinium in Healthy Adults Deficient in CYP2D6 Activity: A Double-Blind, Randomized Clinical Trial

BackgroundUmeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99xa0% of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.ObjectiveThe objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.MethodsThis was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7xa0days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [nxa0=xa020] and poor CYP2D6 metabolizers (HVT-PMs) [nxa0=xa016] participated in the study. The subjects received umeclidinium (100–1,000xa0μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.ResultsThirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration–time curve over the dosing interval (from 0 to 24xa0h for the once-daily drug) [AUCτ (ng·h/mL)] and the maximum plasma concentration [Cmax (ng/mL)] ratios (with 90xa0% confidence intervals [CIs]) following repeat dosing with 500xa0μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79–1.34) and 0.80 (0.59–1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24xa0h (Ae24) [ng] ratio was 1.01 (0.82–1.26). Following repeat dosing with umeclidinium 1,000xa0μg, the plasma AUCτ [ng·h/mL] and Cmax (ng/mL) ratios (with 90xa0% CIs) were 1.33 (0.98–1.81) and 1.07 (0.76–1.51); the urine Ae24 (ng) ratio was 1.47 (1.15–1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.ConclusionUmeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations.

Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

Background Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney. Objectives To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol. Methods Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 μg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 μg. Results No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%–93%) and 89% (81%–93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 μg and umeclidinium/vilanterol 125/25 μg administration, respectively. Treatments were well tolerated in both populations. Conclusion Umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment.

Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects.

AbstractThe long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting β2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia’s correction (QTcF). 103 subjects were enrolled and 86 (83xa0%) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1–10: nxa0=xa077 subjects received placebo, nxa0=xa076 UMEC 500xa0µg, nxa0=xa078 UMEC/VI 125/25xa0µg, or nxa0=xa076 UMEC/VI 500/100xa0µg; day 10: nxa0=xa074 oral tablet moxifloxacin 400xa0mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was −2.38xa0ms (90xa0% prediction interval [PI] −3.82, −0.85) with UMEC 500xa0µg and −0.50xa0ms (90xa0% PI −0.80, −0.18) and −2.01xa0ms (90xa0% PI −3.22, −0.72) with UMEC/VI 125/25xa0µg and 500/100xa0µg, respectively. For VI, estimates were 5.89xa0ms (90xa0% PI 4.89, 6.91) and 7.23xa0ms (90xa0% PI 5.88, 8.55) with UMEC/VI 125/25xa0µg and 500/100xa0µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25xa0µg (5.39xa0ms [90xa0% PI 4.40, 6.47]) and 500/100xa0µg (5.22xa0ms [90xa0% PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.n

Systemic Exposures of Fluticasone Propionate and Salmeterol Following Inhalation via Metered Dose Inhaler with the Mini Spacer Compared with the Aerochamber Plus Spacer

BACKGROUNDnThe Mini Spacer has been developed for use with Ventolin(®) metered dose inhalers (MDIs) to improve accessibility to affordable spacers in developing countries. To ensure patient safety is not compromised if the Mini Spacer is used off-label with fluticasone propionate (FP) or salmeterol/FP combination (SFC) MDIs (currently not recommended), this study compared the systemic exposure of FP and salmeterol following delivery of FP and SFC MDIs with the Mini Spacer and the Aerochamber Plus(®) spacer (Aerochamber).nnnMETHODSnThis was an open-label, randomized, single dose, crossover study in healthy subjects that evaluated four treatments: i) FP 250u2009μg MDI with Mini Spacer; ii) FP 250u2009μg MDI with Aerochamber; iii) SFC 25/250u2009μg with Mini Spacer; iv) SFC 25/250u2009μg with Aerochamber. There was a minimum 7 day washout between treatments. Pharmacokinetic samples were collected over 24 hours post-dose. The co-primary endpoints were FP area under the concentration-time curve from time zero to 24u2009h [FP AUC(0-24)] and salmeterol maximum plasma concentration [Cmax].nnnRESULTSnFP systemic exposure in terms of AUC(0-24) was lower following inhalation with the Mini Spacer compared with the Aerochamber for both FP 250u2009μg (Mini Spacer/Aerochamber Ratio 0.76 [90% CI: 0.57-1.01]) and SFC 25/250u2009μg (Ratio 0.74 [90% CI: 0.56-0.99]). Salmeterol systemic exposure was also lower following SFC 25/250u2009μg with Mini Spacer compared with Aerochamber (Cmax Ratio 0.90 [90% CI 0.48-1.66]). The incidence of adverse events was low and similar with each treatment.nnnCONCLUSIONSnIn the event of use of the Mini Spacer with FP and SFC MDIs, which is not recommended, FP and salmeterol systemic exposure is unlikely to be higher than if MDIs were to be used with the Aerochamber. However, these data do not indicate that the Mini Spacer and Aerochamber are interchangeable.