Urine concentrations of vilanterol and its metabolites, GSK932009 and GW630200, after inhalation of therapeutic and supratherapeutic doses.

The 2023 Prohibited List issued by the World Anti-Doping Agency (WADA) permits athletes to inhale the beta2 -agonist vilanterol at a standard dose of 25 µg daily. However, given limited data on urine pharmacokinetics, vilanterol has no urinary threshold or decision limit to discriminate therapeutic from supratherapeutic use. We investigated urine concentrations of vilanterol and its main metabolites GSK932009 and GW630200 over 0-72 h following inhalation of therapeutic (25 µg) or supratherapeutic (100 µg) doses and repeat-dose administration for 7 days of 25 or 100 µg·day-1 in 25 trained men and women. Vilanterol administration was followed by 1 h of exercise. GW630200 urine concentrations were low and insufficient for threshold purposes, and while GSK932009 had higher urine concentrations, it could not discriminate between therapeutic and supratherapeutic use. Mean (range) maximum urine concentrations of parent vilanterol were 1.2 (0.2-4.1) and 6.2 (1.4-14.3) ng·ml-1 for single-dose 25 and 100 µg vilanterol, respectively, and 2.0 (0.3-4.8) and 22.4 (6.4-42.1) ng·ml-1 for repeat-dose 25 and 100 µg·day-1 vilanterol. In 333 samples collected 6 h post-administration and considering WADA TD2022DL, a 3.1 ng·ml-1 vilanterol cut-off showed 30% sensitivity in detecting supratherapeutic use at 100 µg versus therapeutic use at 25 µg. Considering inter- and intra-individual variability and guard bands in doping analysis, a 6 ng·ml-1 decision limit, which could be shifted upwards in samples with specific gravity >1.018, appears sufficiently high to minimize risk of samples exceeding the decision limit after therapeutic use of vilanterol, while demonstrating the ability to detect supratherapeutic use at 100 µg.

Integrated Assessment of Bioconcentration, Toxicity, and Hazards of Chlorobenzenes in the Aquatic Environment.

The evaluation of bioconcentration, toxicity, and hazard (BTH) of persistent lipophilic organic compounds (LOCs) are generally performed as separate rather than integrated assessments. There are adequate data sets in the literature for chlorobenzenes (CBs) consisting of (a) concentrations in aquatic biota (CB) and water (Cw) in the natural environment, (b) laboratory-derived bioconcentration factors (KB) and field concentration ratios (CR), the field equivalent factor of KB, (c) measured internal lethal concentrations (ILC50) and model estimated ILC50 calculated from KB and lethal concentrations (LC50), and (d) calculated hazard quotients in aquatic biota (HQB) and in water (HQW). However, there have been no integrated studies of those parameter values based on the respective lipid-based parameters (CBL, KBL, CRL, ILC50L, HQBL) performed. This study utilized the lipid-based parameters for CBs; a group of widely occuring, bioaccumulative, and toxic LOCs, and integrated those parameters into a bioconcentration-toxicity-hazard (BTHL) index. The values of the parameters were obtained from selected literature with known lipid contents of the aquatic biota. The results showed that the laboratory derived bioconcentration factors, KBLs, were comparable to the corresponding field based factors, CRLs, and the measured internal lethal concentrations, ILC50L, showed comparable values with the estimated ones. The integrated BTHL index was less than an order of magnitude or moderately acceptable for the assessment of variability, uncertainty, and predictive power of the index. This integrated assessment can be used to support decision making dealing with CBs in specific and LOCs in general, both in regional and global aquatic environments.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. METHODS: Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®. RESULTS: The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. CONCLUSIONS: All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

HPLC-UV and spectrofluorimetric methods for simultaneous estimation of fluticasone furoate and vilanterol in rabbit plasma: A pharmacokinetic study.

Fluticasone furoate (FF) and vilanterol trifenatate (VT) is a widely prescribed combination in the management of asthma and chronic obstructive pulmonary disease. In the present study, two quantitative methods based on HPLC-UV and spectrofluorimetric analysis had been developed and validated for simultaneous estimation of FF and VT in rabbit plasma using baclomethasone as internal standard (ISTD). Analytes and ISTD were separated from plasma using simple step of protein precipitation with acetonitrile. Chromatographic separation was achieved on Spherisorb S5 ODS2 (250 mm × 4.6 mm, 5.0 µm) column using mobile phase that constitute acetonitrile-0.01% glacial acetic acid in water (70:30, v/v) and then detected on a UV detector at 235 nm wavelength. Spectrofluorimetric detection was performed using absorption/emission wavelength (λabs/em) of 286/352 nm and 362/407 nm for FF and VT, respectively. For both analytes, linearity ranged from 4-200 ng/mL to 10-200 ng/mL using HPLC-UV and spectrofluorimetric method, respectively. Methods were validated as per FDA recommendations. Statistical analysis revealed that these detection methods are statistically insignificant difference and can be used interchangeably without any bias. Further, these methods were applied in pharmacokinetic study for simultaneous estimation of FF and VT in rabbit plasma.

Fixed-dose combination of umeclidinium and vilanterol for patients with chronic obstructive pulmonary disease: A systematic review.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is predicted to be one of the leading causes of death worldwide. Pharmacologic treatment options of COPD are bronchodilators, using either long-acting ß2-agonists (LABAs), or long-acting muscarinic antagonists (LAMAs), or a combination of two. Anoro Ellipta (umeclidinium + vilanterol) dry powder inhaler, a fixed-dose combination of LAMA and LABA, was Food and Drug Administration (FDA) approved in 2013 for COPD. The objective of this study is to evaluate the efficacy and safety of once daily umeclidinium/vilanterol (62.5 mcg/25 mcg) in COPD patients, focusing on pharmacodynamic and pharmacokinetic characteristics, efficacy and safety in clinical studies and cost. Literature search was done through PubMed (2004-2017) using the terms umeclidinium, vilanterol, COPD, LABA and LAMA. Recent and significant clinical trials about the monocomponents and their combination were identified, in addition to reviews, guidelines for COPD, data from manufacturer and FDA product labels. The search was limited to English language studies on human subjects. Clinical data published on the combination of umeclidinium/vilanterol in patients with COPD have shown greater improvements in lung function compared to monotherapies. However, further studies comparing umeclidinium/vilanterol FDC (ANORO) to other LABA/LAMA combinations are needed.

Evidence-based review of data on the combination inhaler umeclidinium/vilanterol in patients with COPD.

The use of inhaled, fixed-dose, long-acting muscarinic antagonists (LAMA) combined with long-acting, beta2-adrenergic receptor agonists (LABA) has become a mainstay in the maintenance treatment of chronic obstructive pulmonary disease (COPD). One of the fixed-dose LAMA/LABA combinations is the dry powder inhaler (DPI) of umeclidinium bromide (UMEC) and vilanterol trifenatate (VI) (62.5 µg/25 µg) approved for once-a-day maintenance treatment of COPD. This paper reviews the use of fixed-dose combination LAMA/LABA agents focusing on the UMEC/VI DPI inhaler in the maintenance treatment of COPD. The fixed-dose combination LAMA/LABA inhaler offers a step beyond a single inhaled maintenance agent but is still a single device for the COPD patient having frequent COPD exacerbations and persistent symptoms not well controlled on one agent. Currently available clinical trials suggest that the once-a-day DPI of UMEC/VI is well-tolerated, safe and non-inferior or better than other currently available inhaled fixed-dose LAMA/LABA combinations for COPD.

Pharmacokinetics of Single and Repeat Doses of Fluticasone Furoate/Umeclidinium/Vilanterol in Healthy Chinese Adults.

The pharmacokinetics (PK) and safety of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) after single and repeat dosing in healthy Chinese adults were assessed. In this open-label study (NCT02837380), subjects received once-daily FF/UMEC/VI 100/62.5/25 µg on day 1 and repeat doses on days 2-7. PK parameters (days 1 and 7) included maximum observed concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero (predose) to last time of quantifiable concentration (AUC0-t ). Terminal phase half-life (t½ ) on day 1 was estimated. The primary objective was to assess systemic exposure of FF 100 µg, UMEC 62.5 µg, and VI 25 µg following single-inhaler triple therapy on days 1 and 7. On day 1, geometric mean t½ of UMEC and VI was 0.36 and 0.52 hours, respectively; t½ of FF was not representative because of nonquantifiable concentration data. On days 1 and 7, geometric mean Cmax of FF was 10.46 and 27.32 pg/mL, respectively; Cmax of UMEC was 144.14 and 241.35 pg/mL, respectively; and Cmax of VI was 120.42 and 196.78 pg/mL, respectively. AUC0-t of FF was 1.77 and 276.96 pg·h/mL, respectively; AUC0-t of UMEC was 28.44 and 117.19 pg·h/mL, respectively; and AUC0-t of VI, 42.46 and 101.12 pg·h/mL, respectively. The PK of FF/UMEC/VI was as expected for the individual-component PK previously reported in healthy Chinese adults. No new safety signals were observed.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD.

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate-umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 µg/62.5 µg/25 µg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 µg/12 µg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthma.

INTRODUCTION: The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting ß2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.

A fugacity-based toxicokinetic model for narcotic organic chemicals in fish.

A novel dynamic fugacity-based model is described, developed, and tested that simulates the uptake of narcotic organic chemicals in fish from water as occurs in aquatic bioconcentration and toxicity tests. The physiologically based toxicokinetic model treats the time course of chemical distribution in 4 compartments (tissue groups) in the fish, including the liver, in which biotransformation may occur. In addition to calculating bioconcentration and toxicokinetics, 5 possible toxic endpoints are defined corresponding to chemical concentration, fugacity, or activity reaching a critical value that causes 50% mortality. The mathematical description of multicompartment uptake is simplified by expressing the equations in the fugacity format. The model is parameterized and tested against reported empirical data for the bioconcentration of pentachloroethane in rainbow trout and for uptake and mortality from aquatic exposures to naphthalene and 1,2,4-trichlorobenzene in fathead minnows. Model performance is evaluated, and it is concluded that with suitable parameterization it has potential for application for assessment of both bioconcentration and toxicity expressed as median lethal concentrations, critical body residues, and chemical activity as a function of time to death.

Population pharmacokinetics of inhaled fluticasone furoate and vilanterol in adult and adolescent patients with asthma.

OBJECTIVES: Population pharmacokinetic (PK) methods were used to characterize the PK of fluticasone furoate (FF) and vilanterol (VI) in patients with asthma following once daily inhaled FF/VI and FF and to identify significant covariates that impact the PK. MATERIALS AND METHODS: Four of the five studies in the meta-analysis were conducted in patients with asthma (> 90%), the fifth in healthy subjects. FF data were described by a two-compartment model with first order absorption and elimination. VI data were described by a three-compartment model with zero-order absorption and first order elimination. RESULTS: Race was a significant covariate on inhaled clearance (CL/F) of FF PK. AUC(0-24) for Asian patients was on average 33 - 53% higher than for non-Asians. Race was also a significant covariate on VI PK, with lower (81%) central volume of distribution (Vc/F) for Asian patients compared with non-Asians; VI C(max) was 220 - 287% higher in Asian patients. Treatment (combination or monotherapy), predicted percentage FEV(1), and other demographic variables did not influence the PK of FF or VI. CONCLUSIONS: Combination of FF/VI does not appear to affect the PK of FF or VI. The effect of race on PK of FF or VI does not have impact on dosage adjustments for FF/VI in East Asian patients with asthma.

Population Pharmacokinetics of Inhaled Fluticasone Furoate and Vilanterol in Subjects with Chronic Obstructive Pulmonary Disease.

BACKGROUND AND OBJECTIVES: Previous pharmacokinetic studies of the inhaled corticosteroid, fluticasone furoate (FF), and the long-acting, beta2-receptor agonist, vilanterol (VI) have been performed in relatively small populations using non-compartmental pharmacokinetic methods and censored data (due to low drug exposure relative to assay sensitivity). This paper presents a population pharmacokinetic analysis, utilizing pooled concentration-time data from clinical studies in healthy subjects and from global trials in patients with chronic obstructive pulmonary disease (COPD). The objective of this analysis was to characterize the population pharmacokinetics of FF and VI following once-daily inhalation dosing of FF/VI or the individual components (FF and VI) and to identify significant covariates that impact systemic exposure to FF and VI in this population. METHODS: Population pharmacokinetic methods that maximize the likelihood of all data were developed to describe systemic exposure to FF and VI following once-daily FF/VI, FF, or VI, and to identify significant covariates that impact the pharmacokinetics. COPD patients (N = 1225 for the FF analysis and N = 1091 for the VI analysis; 94 and 93 % of total data, respectively) and healthy subjects contributed to the analysis. RESULTS: FF data were described by a two-compartment model with first-order absorption and elimination. The population grouping "race" was a significant covariate on inhaled clearance (CL/F). The area under the curve over 24 h (AUC0-24) for FF was higher for East Asian, Japanese, and South East Asian (average 23-30 %) and Asian Central, White Arabic, American Indian/Native Alaskan, and 'other' (10-26 %) subjects compared with White/Caucasians. VI pharmacokinetics were described by a three-compartment model with zero-order absorption and first-order elimination. Significant demographic covariates identified to affect pharmacokinetics of VI were age [on CL/F and central volume (V 1/F)], bodyweight (on CL/F), sex and smoking (on V 1/F). CONCLUSIONS: While significant effects of the covariates were observed in this study, the magnitude of these effects on systemic exposure is not large enough to warrant FF/VI dosage adjustment in patients with COPD.

Pharmacokinetics and Systemic Activity of a New Patent of an Inhaled Corticosteroid/Long-Acting ß2-Agonist Combination for Use in Asthma Therapy: Fluticasone Furoate/Vilanterol Trifenatate.

The present paper reviews pharmacokinetics and systemic activity of a new patent of fluticasone fumarate/vilanterol trifenatate and summarises the efficacy data in children, adolescents and adults with asthma. Bioavailability of oral deposition of fluticasone furoate is approximately 1%, of oral and pulmonary deposition 15%. Fluticasone furoate 400, 600 and 800 µg have been associated with reductions in 24h urine cortisol excretion in adults, whereas several studies on fluticasone furoate/ vilanterol trifenatate 100/25 µg and 200/25 µg once daily found no suppressive effects. Bronchodilation was detected in adults with asthma from 5 minutes after vilanterol trifenatate was inhaled and up to 24 hours after. Five large clinical trials which were sponsored by the manufacturer GlaxoSmithKline provided evidence that dry powder fluticasone furoate/vilanterol trifenatate 100/25 µg and 200/25 µg once daily are efficacious in asthma in patients ≥ 12 years of age. It remains to be proven, however, that once daily dosing may improve asthma control as compared to twice daily dosing. Efficacy and the systemic activity potential for hypothalamic-pituitary-adrenal and growth suppression of fluticasone furoate have not been established in children. The potential for systemic activity of fluticasone furoate in children may be assessed by knemometry.

Fluticasone furoate/vilanterol combination for the treatment of COPD and asthma.

The critical role of the combination therapy of an inhaled corticosteroid (ICS) and a long-acting ß-adrenoceptor agonist (LABA) in the treatment of patients suffering from asthma and also severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations explains why there is a strong interest within the pharmaceutical industry in developing a once-daily ICS/LABA fixed-dose combination (FDC), in an attempt to simplify the treatment and, consequently, increase adherence to the prescribed therapy, and also to overcome the loss of patent protection. GlaxoSmithKline and Theravance have developed an inhaled FDC of the ICS fluticasone furoate (FF) and the LABA vilanterol (VI) as a once-daily treatment for asthma and COPD. FF/VI, by simplifying the dosing schedule, allows, for the first time, a shift from twice-daily to once-daily treatment, with an acceptable safety and tolerability profile that is consistent with the ICS/LABA class. The decision to prescribe FF/VI rather than another ICS/LABA FDC is likely to be based on the patient's preference for the inhaler device, their ability to use the device correctly and the convenience of once-daily dosing frequency as well as comparative costs with other combination products. However, further studies are required to specifically assess these possibilities.

Tissue distribution, excretion, and the metabolic pathway of 2,2',4,4',5-penta-chlorinated diphenylsulfide (CDPS-99) in ICR mice.

The tissue distribution, excretion, and metabolic pathway of 2,2',4,4',5-penta-chlorinated diphenylsulfide (CDPS-99) in ICR mice were investigated after oral perfusion at 10mg/kg body weight (b.w.). Biological samples were extracted and separated and, for the first time, were determined by a novel, sensitive, and specific GC-MS method under the full scan and selected ion monitoring (SIM) modes. The results showed that the concentrations of CDPS-99 in the liver, kidneys, and serum reached a maximum after a one-day exposure and that the CDPS-99 concentration in the liver was the highest (3.43µg/g). The increase in the concentration of CDPS-99 in muscle, skin, and adipose tissue was slower, and the concentrations of CDPS-99 achieved their highest levels after 3 days of exposure. It was observed that the CDPS-99 concentration in adipose tissue was still very high (0.71µg/g) after 21 days of exposure, which suggested that CDPS-99 was able to accumulate in adipose tissue. In addition, mouse feces accounted for approximately 75% of the total gavage dose, indicating that CDPS-99 was mainly excreted via mouse feces. Metabolism analysis demonstrated that there were three possible metabolic pathways of CDPS-99 in mice: dechlorination reactions with the formation of tetra-CDPS and hydroxylation and oxidation reactions with the formation of OH-CDPS-99 and chlorinated diphenylsulfone. The present study will help to develop a better understanding of mammalian metabolism of CDPS-99.

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 ELLIPT® 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.

Pharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjects.

STUDY OBJECTIVE: To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting ß2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects. DESIGN: Double-blind, placebo-controlled, single-site, randomized, four-way crossover study. SETTING: The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. SUBJECTS: Sixteen healthy, nonsmoking Chinese adults. INTERVENTION: Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 µg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period. MEASUREMENTS AND MAIN RESULTS: The co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting ß2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 µg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 µg but not with 200/25 µg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 µg on day 1 and FF/VI 50/25 and 200/25 µg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 µg ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. CONCLUSION: In healthy Chinese subjects, minimal and non-clinically relevant ß-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 µg. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 µg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 µg.

Pharmacokinetics and tolerability of inhaled umeclidinium and vilanterol alone and in combination in healthy Chinese subjects: a randomized, open-label, crossover trial.

UNLABELLED: Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 µg (delivering 55/22 µg) and UMEC/VI 125/25 µg (delivering 113/22 µg) compared with their monotherapy components (UMEC 62.5 µg, UMEC 125 µg and, VI 25 µg [delivering 55, 113, and 22 µg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2­4 h for UMEC and 1­2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11­34% based on Cmax and 19­59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25­66% based on Cmax and 17­43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01899638 NCT01899638.

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.

Determining high-quality critical body residues for multiple species and chemicals by applying improved experimental design and data interpretation concepts.

Ecotoxicological effect data are generally expressed as effective concentrations in the external exposure medium and do thus not account for differences in chemical uptake, bioavailability, and metabolism, which can introduce substantial data variation. The Critical Body Residue (CBR) concept provides clear advantages, because it links effects directly to the internal exposure. Using CBRs instead of external concentrations should therefore reduce variability. For compounds that act via narcosis even a constant CBR has been proposed. Despite the expected uniformity, CBR values for these compounds still show large variability, possibly due to biased and inconsistent experimental testing. In the present study we tested whether variation in CBR data can be substantially reduced when using an improved experimental design and avoiding confounding factors. The aim was to develop and apply a well-defined test protocol for accurately and precisely measuring CBR data, involving improved (passive) dosing, sampling, and processing of organisms. The chemicals 1,2,4-trichlorobenzene, 1,2,3,4-tetrachlorobenzene, 2,3,4-trichloroaniline, 2,3,5,6-tetrachloroaniline, 4-chloro-3-methylphenol, pentylbenzene, pyrene, and bromophos-methyl were tested on Lumbriculus variegatus (California blackworm), Hyalella azteca (scud), and Poecilia reticulata (guppy), which yielded a high-quality database of 348 individual CBR values. Medians of CBR values ranged from 2.1 to 16.1 mmol/kg wet weight (ww) within all combinations of chemicals and species, except for the insecticide bromophos-methyl, for which the median was 1.3 mmol/kg ww. The new database thus covers about one log unit, which is considerably less than in existing databases. Medians differed maximally by a factor of 8.4 between the 7 chemicals but within one species, and by a factor of 2.6 between the three species but for individual chemicals. Accounting for the chemicals' internal distribution to different partitioning domains and relating effects to estimated concentrations in the target compartment (i.e., membrane lipids) was expected to but did not decrease the overall variability, likely because the surrogate partition coefficients for membrane lipid, storage lipid, protein, and carbohydrate that were used as input parameters did not sufficiently represent the actual partitioning processes. The results of this study demonstrate that a well-designed test setup can produce CBR data that are highly uniform beyond chemical and biological diversity.