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1.
Clin Ther ; 41(6): 1110-1127, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060740

RESUMO

PURPOSE: Pulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies. METHODS: This 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (Cmax, AUC0-∞, and AUC0-t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data. FINDINGS: Of the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported. IMPLICATIONS: An ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.

2.
Value Health ; 22(3): 340-347, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30832972

RESUMO

INTRODUCTION: Diary-derived symptom score and rescue medication use endpoints, such as symptom-free days (SFDs) and rescue medication-free days (RFD), are frequently used as clinical trial endpoints. Estimates of meaningful change for SFDs and RFDs have not been generated in pediatric populations. This research aimed to generate evidence supporting estimates of the individual within-patient changes that constitute an important or meaningful change in SFDs, RFDs, and updated estimates on the Childhood Asthma Control Test (C-ACT) in pediatric asthma populations aged 5-11 years. METHODS: Semistructured, qualitative interviews were conducted with children (ages 8-11 years) who had asthma and parents/caregivers of children (4-11 years) with asthma. Before the interview (4-9 days) participants were asked to complete a morning and evening diary. RESULTS: On average, parent/caregiver estimates of the difference in SFDs between a "very bad" and a "little bad" week for their children's asthma were largely concordant with the values reported by their children (differences of 1.8 and 1.4 SFDs, respectively). Both parents/caregivers and children were able to articulate what a meaningful level of change would be on the C-ACT at the item level. This qualitative study generated C-ACT item-level meaningful change estimates in the region of 1-3 category change, which potentially suggests that, if scaled up to represent C-ACT total score, this would lead to change estimates of 7-15 points. CONCLUSIONS: Our findings suggest that both children with asthma and parents/caregivers can quantitatively estimate and to some extent qualitatively articulate meaningful change in SFDs and RFDs.


Assuntos
Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/normas , Ensaios Clínicos Fase IV como Assunto/normas , Uso Significativo/normas , Asma/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Uso Significativo/tendências , Registros Médicos/normas
3.
J Pharmacol Exp Ther ; 367(3): 405-413, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30217958

RESUMO

Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n = 50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 ml; 95% credible interval -83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0-4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3Kδ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate.

5.
Clin Ther ; 39(6): 1191-1199, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28545804

RESUMO

PURPOSE: A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. METHODS: Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 µg and placebo once daily in the evening. Lower leg length was measured by using knemometry. FINDINGS: The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5-11) years; 58% had a duration of asthma ≥5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was -0.052 mm/week with a 95% CI of -0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of -0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF. IMPLICATIONS: Inhaled FF 50 µg provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 µg was well tolerated in this study population. ClinicalTrials.gov identifier: NCT02502734.


Assuntos
Androstadienos/uso terapêutico , Asma/tratamento farmacológico , Desenvolvimento Infantil/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Perna (Membro)/crescimento & desenvolvimento , Administração por Inalação , Criança , Pré-Escolar , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Humanos , Masculino , Resultado do Tratamento
6.
ERJ Open Res ; 2(2)2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27730198

RESUMO

This study compared the efficacy and safety of once-daily umeclidinium 62.5 µg with once-daily glycopyrronium 50 µg in patients with moderate-to-severe chronic obstructive pulmonary disease. This was a 12-week, multicentre, randomised, open-label, parallel-group study (Clinicaltrials.gov: NCT02236611). Patients were randomised 1:1 to umeclidinium 62.5 µg or glycopyrronium 50 µg administered via Ellipta or Breezhaler dry powder inhaler, respectively. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at day 85 in the per-protocol population. Other endpoints included: weighted mean FEV1 over 0-24 h and patient-reported outcomes (transition dyspnoea index score and St George's Respiratory Questionnaire total score). Adverse events were also assessed. A total of 1037 patients were randomised to treatment. Umeclidinium was non-inferior (margin: -50 mL) to glycopyrronium (trough FEV1 at day 85 treatment difference: 24 mL, 95% confidence intervals: -5-54). Improvements in other endpoints were similar between treatments. Adverse event incidences were similar for umeclidinium (37%) and glycopyrronium (36%). Once-daily umeclidinium was non-inferior to once-daily glycopyrronium in patients with chronic obstructive pulmonary disease in trough FEV1 at day 85. Patient-reported outcomes and safety profiles were similar for both treatments.

7.
Clin Pharmacol Drug Dev ; 5(4): 285-95, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27310329

RESUMO

This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the ß2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 µg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 µg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Indanos/administração & dosagem , Pulmão/metabolismo , Pregnadienodiois/administração & dosagem , Quinolonas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Carvão Vegetal/química , Estudos Cross-Over , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Masculino , Nebulizadores e Vaporizadores , Pregnadienodiois/efeitos adversos , Pregnadienodiois/farmacocinética , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Distribuição Tecidual , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-27103795

RESUMO

BACKGROUND: The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD. METHODS: This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 µg plus placebo or TIO 18 µg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at day 85 (non-inferiority margin -50 mL; per-protocol [PP] population). Other end points included weighted mean FEV1 over 0-24 and 12-24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George's Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed. RESULTS: In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29-88; P<0.001). Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 (53 mL, 95% CI: 25-81; P<0.001). Improvements in weighted mean FEV1 over 0-24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12-24 hours post-dose (70 mL; P=0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George's Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO. CONCLUSION: UMEC 62.5 µg demonstrated superior efficacy to TIO 18 µg on the primary end point of trough FEV1 at day 85. Safety profiles were similar for both treatments.


Assuntos
Antagonistas Colinérgicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinuclidinas/efeitos adversos , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento
9.
Pulm Pharmacol Ther ; 37: 30-6, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26845343

RESUMO

PURPOSE: QMF149 is a fixed-dose combination of the long-acting ß2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 µg/mometasone furoate 320 µg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.


Assuntos
Corticosteroides/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Indanos/farmacocinética , Pregnadienodiois/farmacocinética , Quinolonas/farmacocinética , Administração por Inalação , Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Interações de Medicamentos , Feminino , Humanos , Indanos/administração & dosagem , Masculino , Furoato de Mometasona/administração & dosagem , Furoato de Mometasona/farmacocinética , Pregnadienodiois/administração & dosagem , Quinolonas/administração & dosagem
10.
Eur Respir J ; 46(3): 783-94, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26113676

RESUMO

Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day(-1) escalated to 10 mg·day(-1)) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (-111-132) and 114 mL (11-217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL(-1) to 934.5 pg·mL(-1), and 103 ng·mL(-1) to 80.5 ng·mL(-1), respectively. Adverse events were mostly grade 1-2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe.


Assuntos
Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/tratamento farmacológico , Fator D de Crescimento do Endotélio Vascular/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Intervalos de Confiança , Relação Dose-Resposta a Droga , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Linfangioleiomiomatose/patologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Medição de Risco , Resultado do Tratamento , Fator D de Crescimento do Endotélio Vascular/sangue , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologia , Adulto Jovem
11.
Int J Clin Pharmacol Ther ; 53(5): 398-407, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25740265

RESUMO

OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.


Assuntos
Antiasmáticos/farmacocinética , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Indanos/farmacocinética , Pregnadienodiois/farmacocinética , Quinolonas/farmacocinética , Administração por Inalação , Adulto , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Antiasmáticos/sangue , Área Sob a Curva , Estudos Cross-Over , Combinação de Medicamentos , Monitoramento de Medicamentos , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Indanos/sangue , Japão , Masculino , Nebulizadores e Vaporizadores , Pregnadienodiois/administração & dosagem , Pregnadienodiois/efeitos adversos , Pregnadienodiois/sangue , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Quinolonas/sangue , Adulto Jovem
12.
Eur J Drug Metab Pharmacokinet ; 40(2): 203-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24705947

RESUMO

Indacaterol is an inhaled, ultra-long-acting ß2-agonist that provides 24-h bronchodilation with once-daily dosing in patients with chronic obstructive pulmonary disorder. This study evaluated the pharmacokinetics, safety, and tolerability of multiple daily inhaled doses of indacaterol 150 or 300 µg once daily in healthy Chinese volunteers. This was a single-center, randomized, double-blind, multiple-dose, parallel-group study, placebo-controlled trial including two doses of indacaterol: 150 and 300 µg. Serum indacaterol was quantified using high-performance liquid chromatography-mass spectrometry with a lower limit of quantification of 0.01 ng/mL. The pharmacokinetic parameters were analyzed using non-compartmental analysis and included C max, T max, and AUC0-24h on Day 1 and AUC0-24h,ss, C max,ss, C min,ss, C av,ss, T max,ss, T 1/2, T 1/2,acc, CL/F, V z/F, and R acc on Day 14 (after repeated once-daily doses). Safety analyses were recorded using physical examination, biochemical tests, and ECG. Indacaterol steady state was achieved after 12-14 days of daily dosing. The mean effective half-life of indacaterol (based on drug accumulation at steady state) was 33.9 and 35.8 h for 150 and 300 µg, respectively. Systemic exposure to indacaterol increased 1.27 and 1.34-fold between the 150- and 300-µg doses on Day 1 (first dose) and Day 14 (repeated dose), respectively. Indacaterol 150 and 300 µg were safe and well tolerated in these volunteers. The pharmacokinetics of multiple inhaled doses of indacaterol 150 and 300 µg (for 14 days) were consistent with moderate systemic accumulation at steady state after repeated once-daily inhalation in healthy Chinese volunteers.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Indanos/farmacocinética , Quinolonas/farmacocinética , Administração por Inalação , Adulto , Método Duplo-Cego , Feminino , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Masculino , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Adulto Jovem
13.
J Aerosol Med Pulm Drug Deliv ; 28(4): 268-80, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25517988

RESUMO

BACKGROUND: Establishing robust in vitro-in vivo correlations (IVIVC) between aerosol performance, pharmacokinetics, and clinical efficacy is critical in developing bioequivalent drug-device combination products. Recent studies have demonstrated that realistic throat models tested under realistic test conditions may provide good IVIVC with respect to total lung deposition. METHODS: The Alberta idealized throat (AIT) model was utilized with mean peak inspiratory flow rates determined from patient breathing studies. Various formulations of indacaterol (e.g., lactose blends, fixed dose combinations, engineered PulmoSphere™ particles) were tested in the AIT model and in clinical pharmacokinetic studies. RESULTS: Good IVIVC were observed with respect to total lung deposition, systemic delivery, and the contribution of oral absorption to systemic delivery, with percentage differences from the mean in vivo measurements <15%, with most comparisons <5%. CONCLUSIONS: Anatomical throat models represent an exciting tool to aid in formulation development of pharmaceutical aerosols.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Sistemas de Liberação de Medicamentos/instrumentação , Inaladores de Pó Seco , Indanos/administração & dosagem , Modelos Anatômicos , Modelos Biológicos , Faringe/anatomia & histologia , Quinolonas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Aerossóis , Disponibilidade Biológica , Broncodilatadores/química , Broncodilatadores/farmacocinética , Química Farmacêutica , Portadores de Fármacos/química , Combinação de Medicamentos , Desenho de Equipamento , Glicopirrolato/administração & dosagem , Humanos , Indanos/química , Indanos/farmacocinética , Lactose/química , Antagonistas Muscarínicos/administração & dosagem , Tamanho da Partícula , Pós , Quinolonas/química , Quinolonas/farmacocinética , Equivalência Terapêutica , Distribuição Tecidual
14.
COPD ; 8(5): 340-5, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21793716

RESUMO

Indacaterol is a novel, inhaled once-daily ultra long-acting ß2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 µg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 ≥ 40% and ≤ 80%, smoking history ≥ 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 µg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 µg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Indanos/uso terapêutico , Capacidade Inspiratória/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Idoso , Estudos Cross-Over , Método Duplo-Cego , Dispneia/tratamento farmacológico , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Indanos/farmacologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/farmacologia , Resultado do Tratamento
15.
BMC Pulm Med ; 11: 31, 2011 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-21615886

RESUMO

BACKGROUND: Indacaterol is a novel once-daily ultra long-acting ß2-agonist for the treatment of chronic obstructive pulmonary disease. It is known that ß2-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects. METHODS: In this randomized, double-blind, parallel-group, placebo- and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index: 18.5-32.0 kg/m2) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 µg, 300 µg, or 600 µg), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericia's formula). RESULTS: In total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 µg [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 µg, 300 µg and 600 µg, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated. CONCLUSION: Indacaterol, at doses up to 600 µg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Eletrocardiografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Indanos/farmacologia , Quinolonas/farmacologia , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Compostos Aza/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluoroquinolonas , Coração/fisiologia , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Quinolinas/farmacologia , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Adulto Jovem
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