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1.
Drug Metab Dispos ; 48(4): 307-316, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32009006

RESUMEN

In vitro data for low-dose inhaled phosphoinositide 3-kinase delta inhibitor nemiralisib revealed that it was a substrate and a potent metabolism-dependent inhibitor of cytochrome P450 (P450) 3A4 and a P-glycoprotein (P-gp) substrate. An integrated in silico, in vitro, and clinical approach including a clinical drug interaction study as well as a bespoke physiologically based pharmacokinetic (PBPK) model was used to assess the drug-drug interaction (DDI) risk. Inhaled nemiralisib (100 µg, single dose) was coadministered with itraconazole, a potent P4503A4/P-gp inhibitor, following 200 mg daily administrations for 10 days in 20 male healthy subjects. Systemic exposure to nemiralisib (AUC0-inf) increased by 2.01-fold versus nemiralisib alone. To extrapolate the clinical data to other P4503A4 inhibitors, an inhaled PBPK model was developed using Simcyp software. Retrospective simulation of the victim risk showed good agreement between simulated and observed data (AUC0-inf ratio 2.3 vs. 2.01, respectively). Prospective DDI simulations predicted a weak but manageable drug interaction when nemiralisib was coadministered with other P4503A4 inhibitors, such as the macrolides clarithromycin and erythromycin (simulated AUC0-inf ratio of 1.7), both common comedications in the intended patient populations. PBPK and static mechanistic models were also used to predict a negligible perpetrator DDI effect for nemiralisib on other P4503A4 substrates, including midazolam (a sensitive probe substrate of P4503A4) and theophylline (a narrow therapeutic index drug and another common comedication). In summary, an integrated in silico, in vitro, and clinical approach including an inhalation PBPK model has successfully discharged any potential patient DDI risks in future nemiralisib clinical trials. SIGNIFICANCE STATEMENT: This paper describes the integration of in silico, in vitro, and clinical data to successfully discharge potential drug-drug interaction risks for a low-dose inhaled drug. This work featured assessment of victim and perpetrator risks of drug transporters and cytochrome P450 enzymes, utilizing empirical and mechanistic approaches combined with clinical data (drug interaction and human absorption, metabolism, and pharmacokinetics) and physiologically based pharmacokinetic modeling approaches to facilitate bespoke risk assessment in target patient populations.


Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indazoles/farmacocinética , Indoles/farmacocinética , Itraconazol/farmacocinética , Oxazoles/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Piperazinas/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Anciano , Área Bajo la Curva , Claritromicina/administración & dosificación , Claritromicina/farmacocinética , Simulación por Computador , Estudios Cruzados , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Voluntarios Sanos , Humanos , Indazoles/administración & dosificación , Indoles/administración & dosificación , Itraconazol/administración & dosificación , Masculino , Microsomas Hepáticos , Midazolam/administración & dosificación , Midazolam/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Oxazoles/administración & dosificación , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Piperazinas/administración & dosificación , Estudios Prospectivos , Estudios Retrospectivos , Adulto Joven
2.
BMC Cancer ; 20(1): 342, 2020 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-32321474

RESUMEN

BACKGROUND: Planar-based measurements of lesions in metastatic melanoma have limitations in estimating tumor burden of a patient and in predicting response to treatment. Volumetric imaging might add predictive value to Response criteria in Solid Tumor (RECIST)-measurement. Based on clinical observations, we explored the association between baseline tumor volume (TV) and duration of treatment with dabrafenib in patients with metastatic melanoma. We have also explored the prognostic value of TV for overall survival (OS) and progression free survival (PFS). METHODS: This is a retrospective, chart-review of primary source documents and medical imaging of a cohort of patients participating in the BRF112680 phase 1 clinical trial at the Prince of Wales Hospital. TV was quantified by contouring all the measurable baseline target lesions in the standard manner for radiation planning using Voxxar™ software. We used Cox regression models to analyse associations between TV and duration of treatment with dabrafenib and between TV, PFS and OS. RESULTS: Among 13 patients of BRAF 112680 trial, 10 were included in the retrospective analysis. Target lesion sum volume ranged from 0.3 to 1065.5 cm3 (cc), with a median of 27.5 cc. The median PFS and OS were 420 days (range 109-1765) and 1680 days (range 390-2940), respectively. The initial TV was inversely correlated with duration of treatment with dabrafenib (rho - 0.6; P 0.03). In multivariate analysis, TV was a predictor for OS (HR 2.81 CI 1.06-6.19) and PFS (8.76 (CI 1.05-43.58). Patients with tumour volume above the median had significantly lower OS of 6-months compared to 56-months survival for patients with smaller volumes; P = 0.019. CONCLUSIONS: TV is a predictor for treatment duration and is prognostic of OS and PFS in patients with metastatic melanoma. These findings need to be validated prospectively in clinical trials.


Asunto(s)
Duración de la Terapia , Imidazoles/uso terapéutico , Melanoma/patología , Mutación , Oximas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Carga Tumoral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/genética , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
3.
Drug Metab Dispos ; 47(12): 1457-1468, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31649125

RESUMEN

An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 µg [14C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 µg dose followed by an oral 800 µg dose of [14C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (Fabs), proportion of nemiralisib escaping gut wall metabolism (Fg), hepatic extraction (Eh), fraction of dose absorbed from inhaled dose (Flung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while Flung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (Fabs, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (Fg and Eh being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (Fabs), the proportion of drug escaping first-pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh). Entero-test bile sampling enabled characterization of biliary elimination pathways.


Asunto(s)
Monitoreo de Drogas/métodos , Indazoles/farmacocinética , Indoles/farmacocinética , Oxazoles/farmacocinética , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Administración por Inhalación , Administración Intravenosa , Administración Oral , Adulto , Disponibilidad Biológica , Radioisótopos de Carbono , Estudios Cruzados , Heces/química , Voluntarios Sanos , Humanos , Indazoles/administración & dosificación , Indazoles/sangre , Indazoles/orina , Indoles/administración & dosificación , Indoles/sangre , Indoles/orina , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Oxazoles/administración & dosificación , Oxazoles/sangre , Oxazoles/orina , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/orina , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/orina , Distribución Tisular
4.
Respir Res ; 19(1): 133, 2018 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-30001712

RESUMEN

BACKGROUND: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action. METHODS: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61-0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 .


Asunto(s)
Androstadienos/administración & dosificación , Antiinflamatorios/administración & dosificación , Asma/diagnóstico , Asma/tratamiento farmacológico , Alcoholes Bencílicos/administración & dosificación , Clorobencenos/administración & dosificación , Adolescente , Adulto , Asma/epidemiología , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Masculino , Estudios Prospectivos , Adulto Joven
5.
J Clin Pharmacol ; 61(1): 125-137, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32820548

RESUMEN

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). To enable administering safe doses of molibresib to healthy volunteers, this 2-part randomized, open-label, crossover drug-drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P-gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15-fold with a 66% increase in Cmax , whereas the total AUC and Cmax for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and Cmax of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2-fold increase in Cmax . The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects.


Asunto(s)
Benzodiazepinas/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Itraconazol/farmacología , Rifampin/farmacología , Adulto , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad
6.
J Aerosol Med Pulm Drug Deliv ; 30(3): 164-172, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28170282

RESUMEN

AIM: To compare the systemic exposure of salbutamol following delivery from the unit dose dry powder inhaler (UD-DPI) system with that from the Diskus® and metered dose inhaler (MDI). MATERIALS AND METHODS: This open-label, two-part, six-way crossover, randomized single-dose study in healthy subjects evaluated salbutamol systemic exposure of three dose strengths (using three inhalations: 3 × 150 µg [450 µg], 3 × 200 µg [600 µg], and 3 × 250 µg [750 µg]) and 2% of drug in lactose blends (1.6% and 1.0% [600 µg dose only] by weight) following delivery through the UD-DPI compared with systemic exposure from the Diskus and MDI (600 µg dose). Systemic exposure in the presence of charcoal block was also evaluated. Primary treatment comparisons were area under the concentration-time curve from time zero to 12 hours [AUC0-12] and maximum plasma concentration [Cmax]. RESULTS: Delivery of salbutamol 600 µg from the UD-DPI resulted in total systemic exposure similar to that from the Diskus and approximately half of that from the MDI (AUC0-12 geometric least squares mean ratio [GMR] [90% confidence interval (CI)] for UD-DPI [1.6% blend]/Diskus: 0.91 [0.83-1.00]; UD-DPI [1.6% blend]/MDI: 0.46 [0.42-0.50]. Cmax GMR [90% CI] for UD-DPI [1.6% blend]/Diskus: 1.20 [1.07-1.33]; UD-DPI [1.6% blend]/MDI: 0.58 [0.52-0.64]). Results were consistent between the 1.6% and the 1.0% blends and systemic exposure for the 3 dose strengths of salbutamol (1.6% blend) showed increases that were 12-16% greater than dose proportional. Systemic exposure due to pulmonary absorption (as calculated from AUC0-12 in the presence and absence of charcoal block) was 48% for the UD-DPI, 24% for Diskus, and 37% for MDI of the total salbutamol systemic exposure, and the corresponding estimated lung dose was 65% for the UD-DPI and 34% for the Diskus relative to the MDI. CONCLUSIONS: Salbutamol total systemic exposure following UD-DPI was similar to that from the Diskus and was lower than that following the MDI. The different blend formulations tested resulted in consistent salbutamol systemic exposure. The contribution of the lung and gut to systemic exposure revealed a different profile for the three inhaler platforms. These data suggest that the UD-DPI warrants further evaluation.


Asunto(s)
Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Inhaladores de Polvo Seco , Pulmón/metabolismo , Administración por Inhalación , Adulto , Albuterol/farmacocinética , Área Bajo la Curva , Broncodilatadores/farmacocinética , Estudios Cruzados , Excipientes/química , Femenino , Humanos , Lactosa/química , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Distribución Tisular , Adulto Joven
7.
J Aerosol Med Pulm Drug Deliv ; 30(5): 332-338, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28463040

RESUMEN

BACKGROUND: The unit dose dry powder inhaler (UD-DPI) is being considered as an alternative inhaler platform that, if developed, has the potential to improve access to inhaled respiratory medicines in developing countries. AIM: This study compared the systemic exposure of fluticasone furoate after delivery from the UD-DPI with that from the ELLIPTA® inhaler. METHODS: This open-label, five-way cross-over, randomized, single-dose study in healthy subjects evaluated fluticasone furoate systemic exposure of three dose strengths (using four inhalations), 4 × 80 µg [320 µg], 4 × 100 µg [400 µg], and 4 × 140 µg [560 µg]), and two percentages of drug in lactose blends (0.6% and 0.8% by weight) after delivery from the UD-DPI compared with systemic exposures from the ELLIPTA inhaler (4 × 100 µg [400 µg] dose, 0.8% lactose blend). The primary treatment comparisons were area under the concentration-time curve from time 0 to 6 hours [AUC0-6] and maximum plasma concentration [Cmax]. RESULTS: After single-dose administration of fluticasone furoate, systemic exposure was lower from all UD-DPI formulations versus the ELLIPTA inhaler in terms of both AUC0-6 [AUC0-6 geometric least squares mean (GLM) ratios confidence interval (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.61 (0.55-0.67) and Cmax GLM (90% CI) for: UD-DPI (400 µg 0.8% blend)/ELLIPTA: 0.56 (0.49-0.64)]. Systemic exposures were ∼10% lower for fluticasone furoate UD-DPI for the 0.8% blend versus the 0.6% blend [GLM ratio (90% CI); 0.90 (0.81-1.00) for AUC0-6 and 0.89 (0.77-1.01) for Cmax], and increasing doses of fluticasone furoate from the UD-DPI showed systemic exposures that were approximately dose proportional. All treatments were well tolerated. CONCLUSIONS: Fluticasone furoate systemic exposure was lower from the UD-DPI than from the ELLIPTA inhaler, but the UD-DPI formulations did demonstrate detectable systemic levels and approximate dose proportionality. Together with the good tolerability shown, these data support further evaluation of the UD-DPI as a potential device for delivering inhaled respiratory drugs.


Asunto(s)
Androstadienos/administración & dosificación , Broncodilatadores/administración & dosificación , Sistemas de Liberación de Medicamentos , Administración por Inhalación , Adolescente , Adulto , Androstadienos/farmacocinética , Área Bajo la Curva , Broncodilatadores/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inhaladores de Polvo Seco , Femenino , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Adulto Joven
8.
Clin Pharmacol Drug Dev ; 5(5): 399-407, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27170445

RESUMEN

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.


Asunto(s)
Androstadienos/administración & dosificación , Broncodilatadores/administración & dosificación , Carbamatos/administración & dosificación , Quinolonas/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Androstadienos/farmacocinética , Área Bajo la Curva , Broncodilatadores/farmacocinética , Carbamatos/farmacocinética , Estudios Cruzados , Combinación de Medicamentos , Inhaladores de Polvo Seco , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinolonas/farmacocinética , Adulto Joven
9.
Clin Drug Investig ; 35(5): 319-26, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25805608

RESUMEN

BACKGROUND AND OBJECTIVES: The Rotacaps(®)/Rotahaler(®) system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus(®). The aim of this study was to compare the systemic exposure of SFC 50/100 µg following delivery via the Rotacaps(®)/Rotahaler(®) and the Diskus(®). METHODS: This was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100 µg delivered via the Rotacaps(®)/Rotahaler(®) and Diskus(®), in healthy subjects. Pharmacokinetic sampling was conducted over 12 h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0-τ ) and salmeterol maximum plasma concentration (C max) on the last day of treatment. RESULTS: Following SFC 50/100 µg Rotacaps(®)/Rotahaler(®), fluticasone propionate and salmeterol systemic exposures were comparable with Diskus(®) in terms of both AUC0-τ [geometric mean ratio (GMR) with 90 % confidence interval (CI) of Rotahaler(®)/Diskus(®) for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and C max [GMR (90 % CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90 % CI for the GMRs (Rotahaler(®)/Diskus(®)) ≤1.25]. SFC delivered from both inhalers was well tolerated. CONCLUSIONS: SFC 50/100 µg Rotacaps(®)/Rotahaler(®) showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus(®) for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90 % CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps(®)/Rotahaler(®) product for further clinical development.


Asunto(s)
Broncodilatadores/farmacocinética , Inhaladores de Polvo Seco , Combinación Fluticasona-Salmeterol/farmacocinética , Inhaladores de Dosis Medida , Adulto , Broncodilatadores/efectos adversos , Broncodilatadores/sangre , Estudios Cruzados , Combinación de Medicamentos , Femenino , Combinación Fluticasona-Salmeterol/efectos adversos , Combinación Fluticasona-Salmeterol/sangre , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
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