RESUMO
Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-term clinical trial on the Efficacy and Safety profile of Doxofylline in Asthma (LESDA) study was to investigate the safety and efficacy profile of doxofylline administered for one year in asthmatic patients. LESDA was a multicenter, open-label, Phase III, clinical trial in which adult asthmatic patients received the same treatment (oral doxofylline 400 mg t.i.d.) for one year. Efficacy was assessed through periodic pulmonary function tests and by having the subjects keep monthly records of asthma events rates and use of salbutamol as rescue medication. The rate of adverse events (AEs) was recorded during the study. Three-hundred nine patients were screened and allocated in the study. Doxofylline significantly improved the change from baseline in forced expiratory volume in 1 s (FEV1) (+16.90 ± 1.81%, P < 0.001 vs. baseline). Doxofylline also significantly improved the rate of asthma events (events/day: -0.57 ± 0.18, P < 0.05 vs. baseline) and the use of salbutamol as rescue medication (puffs/day: -1.48 ± 0.25, P < 0.01 vs. baseline). The most common AEs were nausea (14.56%), headache (14.24%), insomnia (10.68%), and dyspepsia (10.03%). There were neither serious AEs nor deaths during or shortly after the study. Concluding, doxofylline is effective and well tolerated when administered chronically in asthmatic patients.
Assuntos
Asma/tratamento farmacológico , Broncodilatadores/efeitos adversos , Broncodilatadores/uso terapêutico , Teofilina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuterol , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Segurança , Teofilina/administração & dosagem , Teofilina/efeitos adversos , Teofilina/sangue , Teofilina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD). METHODS: We conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 µg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks' treatment with BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 µg. PK parameters in both studies included maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 12h (AUC0-12). RESULTS: In the phase I PK study (30 patients), budesonide and glycopyrronium Cmax were comparable after single and chronic dosing of BGF MDI (accumulation ratio [RAC] 95% and 107%, respectively) whereas Cmax for formoterol was slightly higher after chronic dosing (RAC 116%). AUC0-12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an RAC of 126%, 179%, and 143%, respectively. After 7 days' dosing, AUC0-12 and Cmax for all three components of BGF MDI were similar to those in the KRONOS PK sub-study (202 patients) at Week 24. In the latter sub-study, Cmax and AUC0-12 at Week 24 were generally comparable across treatments for budesonide (geometric mean ratios [GMR] of 96%-109% for BGF MDI vs BFF MDI or BUD/FORM DPI), glycopyrronium (GMR of 88%-100% for BGF MDI vs GFF MDI), and formoterol (GMR of 80%-113% for BGF MDI vs GFF MDI or BFF MDI). CONCLUSIONS: Steady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days' dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug-drug or within-formulation PK interactions.
Assuntos
Broncodilatadores/administração & dosagem , Budesonida/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Fumarato de Formoterol/farmacocinética , Glicopirrolato/farmacocinética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , Budesonida/administração & dosagem , Budesonida/sangue , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/sangue , Glicopirrolato/administração & dosagem , Glicopirrolato/sangue , Humanos , Masculino , Inaladores Dosimetrados , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Distribuição AleatóriaRESUMO
PURPOSE: A combined in vitro - in silico methodology was designed to estimate pharmacokinetics of budesonide delivered via dry powder inhaler. METHODS: Particle size distributions from three budesonide DPIs, measured with a Next Generation Impactor and Alberta Idealized Throat, were input into a lung deposition model to predict regional deposition. Subsequent systemic exposure was estimated using a pharmacokinetic model that incorporated Nernst-Brunner dissolution in the conducting airways to predict the net influence of dissolution, mucociliary clearance, and absorption. RESULTS: DPIs demonstrated significant in vitro differences in deposition, resulting in large differences in simulated regional deposition in the central conducting airways and the alveolar region. Similar but low deposition in the small conducting airways was observed with each DPI. Pharmacokinetic predictions showed good agreement with in vivo data from the literature. Peak systemic concentration was tied primarily to the alveolar dose, while the area under the curve was more dependent on the total lung dose. Tracheobronchial deposition was poorly correlated with pharmacokinetic data. CONCLUSIONS: Combination of realistic in vitro experiments, lung deposition modeling, and pharmacokinetic modeling was shown to provide reasonable estimation of in vivo systemic exposure from DPIs. Such combined approaches are useful in the development of orally inhaled drug products.
Assuntos
Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Budesonida/administração & dosagem , Budesonida/farmacocinética , Inaladores de Pó Seco/instrumentação , Administração por Inalação , Broncodilatadores/sangue , Budesonida/sangue , Simulação por Computador , Desenho de Equipamento , Humanos , Técnicas In Vitro , Pulmão/fisiologia , Modelos Biológicos , Tamanho da Partícula , Faringe , Equivalência TerapêuticaRESUMO
Orciprenaline sulphate (ORP) is a direct-acting sympathomimetic with mainly beta-adrenoceptor stimulant activity. It is used as a bronchodilator in the management of reversible airway obstruction. For the first time, a rapid highly sensitive spectrofluorimetric method is described that is relied on measuring the fluorescence spectra of ORP at acidic pH and without addition of any chemical reagents. The relative fluorescence intensity was measured at 310 nm and after excitation at 224 nm. ORP native fluorescence was calibrated in both water and acetonitrile as diluting solvents. The method was designed to estimate the drug in miscellaneous matrices with high accuracy and precision. Linear ranges of calibration curves were 30.0-400.0 ng/ml and 10.0-240.0 ng/ml in water and acetonitrile, respectively. The detection limits were calculated and reached as low as 3.3 and 3.1 ng/ml, respectively, representing the ultra-sensitivity of the proposed method. This result permitted application of this method for spiked human plasma and urine and was used as a preliminary investigation with good percentage recovery (89.4-106.8%). The application was further extended to analyse ORP in its pharmaceutical formulations. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines.
Assuntos
Metaproterenol/análise , Espectrometria de Fluorescência/métodos , Acetonitrilas/química , Broncodilatadores/análise , Broncodilatadores/sangue , Broncodilatadores/urina , Calibragem , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Metaproterenol/sangue , Metaproterenol/urina , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solventes/químicaRESUMO
Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP-compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half-life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12-hr dosing, steady-state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended-release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter-individual variation.
Assuntos
Bronquite Crônica/veterinária , Doenças do Cão/tratamento farmacológico , Teofilina/farmacocinética , Teofilina/uso terapêutico , Animais , Área Sob a Curva , Bronquite Crônica/tratamento farmacológico , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , Broncodilatadores/uso terapêutico , Cães , Feminino , Meia-Vida , Injeções Intravenosas , Masculino , Teofilina/administração & dosagem , Teofilina/sangueRESUMO
OBJECTIVES: The aims of the study were to investigate the potential drug-drug interaction between salbutamol and ambroxol, the bioequivalence of the new fixed-dose combination containing salbutamol and ambroxol compared with co-administration of the two separate formulations, and to describe the safety and tolerability of the fixed-dose combination formulation in healthy Chinese volunteers. MATERIALS AND METHODS: An open-label, single-dose, four-treatment, four-period crossover study for evaluation of drug-drug interaction and bioequivalence (n = 24) was performed. Each participant received salbutamol 4 mg, ambroxol 15 mg, salbutamol 4 mg co-administered with ambroxol 15 mg or fixed-dose combination formulation (salbutamol 4 mg and ambroxol 15 mg). Plasma concentrations of two analytes were determined with the use of validated LC-MS/MS method. Safety and tolerability were assessed by recording adverse events. RESULTS: Co-administration of salbutamol and ambroxol was not associated with a significant influence on single salbutamol or ambroxol pharmacokinetics. After statistical comparisons of log-transformed Cmax and AUC of salbutamol and ambroxol between fixed-dose combination and concomitant treatments, all 90% confidence intervals of geometric mean ratios were within the predefined equivalence range of 80 - 125%. No serious adverse events were reported, and all treatments were safe and well tolerated in Chinese healthy subjects. CONCLUSION: There were no significant drug-drug pharmacokinetic interactions between salbutamol and ambroxol after oral administration. The new formulation was bioequivalent to the co-administration of two drugs in separate dosage forms.â©.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Albuterol/administração & dosagem , Ambroxol/administração & dosagem , Broncodilatadores/administração & dosagem , Expectorantes/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/sangue , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Albuterol/efeitos adversos , Albuterol/sangue , Albuterol/farmacocinética , Ambroxol/efeitos adversos , Ambroxol/sangue , Ambroxol/farmacocinética , Povo Asiático , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , China , Cromatografia Líquida , Estudos Cross-Over , Combinação de Medicamentos , Composição de Medicamentos , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Expectorantes/efeitos adversos , Expectorantes/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Segurança do Paciente , Medição de Risco , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Adulto JovemRESUMO
Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.
Assuntos
Corticosteroides/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/administração & dosagem , Administração por Inalação , Idoso , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Teofilina/efeitos adversos , Teofilina/sangue , Falha de Tratamento , Capacidade Vital/efeitos dos fármacosRESUMO
In community settings, IM injection of 0.3 mg epinephrine (Epi) using an auto-injector is the drug of choice for treatment of anaphylaxis. Previously, a taste-masking (TM) formulation of fast-disintegrating sublingual tablets (FDSTs) was developed in our lab. Also, Epi was micronized (Epi-MC) successfully and reduced the previously achieved bioequivalent sublingual Epi dose to 0.3 mg IM injection by half using non-taste-masked fast-disintegrating sublingual tablets (TM-FDSTs). Our objective for this study was to evaluate the sublingual absorption of Epi-MC using TM-FDST. These sublingual Epi tablets have potential for out-of-hospital treatment of anaphylaxis and are suitable for human studies. TM-FDSTs containing Epi-MC were manufactured by direct compression. The rate and extent of Epi absorption from our developed 20 mg Epi-MC-TM-FDSTs (n = 5) were evaluated in rabbits and compared to the previous result from 20 mg Epi-MC in non-TM-FDSTs and EpiPen® auto-injector. Blood samples were collected over 1 h, and Epi concentrations were measured using HPLC with electrochemical detection. Mean ± SEM AUC0-1 h and Cmax from 20 mg Epi-MC-TM-FDSTs (733 ± 78 ng/ml/min and 30 ± 8 ng/ml) and 20 mg Epi-MC-non-TM-FDSTs (942 ± 109 ng/ml/min and 38 ± 4 ng/ml) were not significantly different (p > 0.05) from each other or from EpiPen® (592 ± 50 ng/ml/min and 28 ± 3 ng/ml) but were significantly higher (p < 0.05) than endogenous Epi after placebo FDSTs (220 ± 32 ng/ml/min and 8 ± 1 ng/ml). Mean ± SD Tmax was not significantly different (p > 0.05) among all formulations. Epi-MC-TM-FDSTs formulation improved Epi absorption twofold and reduced the required bioequivalent dose by 50%, similar to results obtained using non-TM-FDSTs. The incorporation of TM excipients did not interfere with the absorption of Epi-MC.
Assuntos
Epinefrina , Microesferas , Paladar , Animais , Feminino , Coelhos , Administração Sublingual , Anafilaxia/tratamento farmacológico , Anafilaxia/metabolismo , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Avaliação Pré-Clínica de Medicamentos/métodos , Epinefrina/administração & dosagem , Epinefrina/sangue , Excipientes/administração & dosagem , Excipientes/metabolismo , Injeções Intramusculares , Distribuição Aleatória , Comprimidos/química , Paladar/efeitos dos fármacos , Paladar/fisiologiaRESUMO
AIMS: The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. METHODS: Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. RESULTS: A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 ± 0.29 ml kg-1 min-1 , 0.16 ± 0.06 ml kg-1 min-1 and 0.34 ± 0.28 ml kg-1 min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CONCLUSIONS: CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.
Assuntos
Broncodilatadores/sangue , Broncodilatadores/urina , Citocromo P-450 CYP1A2/metabolismo , Teofilina/sangue , Teofilina/urina , Envelhecimento/metabolismo , Apneia/tratamento farmacológico , Broncodilatadores/uso terapêutico , Citocromo P-450 CYP1A2/genética , Feminino , Genótipo , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Teofilina/uso terapêutico , Ácido Úrico/análogos & derivados , Ácido Úrico/urina , Xantinas/urinaRESUMO
Salmeterol (SAL) is a long-acting ß2-adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four-period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered. Plasma concentration-time (C-t) data were initially analysed using classic non-compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (RL ) was set as a parameter in the structural model. The plasma C-t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C-t profiles of salmeterol. The estimated RL value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Asma/metabolismo , Broncodilatadores , Xinafoato de Salmeterol/farmacocinética , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/sangue , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , Estudos Cross-Over , Inaladores de Pó Seco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Xinafoato de Salmeterol/administração & dosagem , Xinafoato de Salmeterol/sangue , Equivalência Terapêutica , Adulto JovemRESUMO
AIMS: Olodaterol is an orally inhaled ß2 -agonist for treatment of chronic obstructive pulmonary disease (COPD). The aims of this population pharmacokinetic (PK) analysis were: (1) to investigate systemic PK and thereby make inferences about pulmonary PK in asthmatic patients, COPD patients and healthy volunteers, and (2) to assess whether differences in pulmonary efficacy might be expected based on pulmonary PK characteristics. METHODS: Plasma and urine data after olodaterol inhalation were available from six clinical trials comprising 710 patients and healthy volunteers (single and multiple dosing). To investigate the relevance of covariates, full fixed-effect modelling was applied based on a previously developed healthy volunteer systemic disposition model. RESULTS: A pulmonary model with three parallel absorption processes best described PK after inhalation in patients. The pulmonary bioavailable fraction (PBIO) was 48.7% (46.1-51.3%, 95% confidence interval) in asthma, and 53.6% (51.1-56.2%) in COPD. In asthma 87.2% (85.4-88.8%) of PBIO was slowly absorbed with an absorption half-life of 18.5 h (16.3-21.4 h), whereas in COPD 80.1% (78.0-82.2%) was absorbed with a half-life of 37.8 h (31.1-47.8 h). In healthy volunteers absorption was faster, with a half-life of 18.5 h (16.3-21.4 h) of the slowest absorbed process, which characterized 74.6% (69.1-80.2%) of PBIO. CONCLUSIONS: The modelling approach successfully described data after olodaterol inhalation in patients and healthy volunteers. Slow pulmonary absorption was demonstrated both in asthma and COPD. Absorption characteristics after olodaterol inhalation indicated even more beneficial lung targeting in patients compared to healthy volunteers.
Assuntos
Asma/metabolismo , Benzoxazinas/farmacocinética , Pulmão/metabolismo , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Administração por Inalação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/sangue , Asma/tratamento farmacológico , Asma/urina , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Benzoxazinas/urina , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Broncodilatadores/farmacocinética , Broncodilatadores/urina , Ensaios Clínicos como Assunto/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/urina , Adulto JovemRESUMO
A rapid, selective and sensitive liquid chromatography-tandem mass spectrometry assay method was developed for simultaneous determination of ambroxol and salbutamol in human plasma using citalopram hydrobromide as internal standard (IS). The sample was alkalinized with ammonia water (33:67, v/v) and extracted by single liquid-liquid extraction with ethyl acetate. Separation was achieved on Waters Acquity UPLC BEH C18 column using a gradient program at a flow rate of 0.2 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring mode by monitoring the ion transitions m/z 378.9 â 263.6 (ambroxol), m/z 240.2 â 147.7 (salbutamol) and m/z 325.0 â 261.7 (IS). The total analytical run time was relatively short (3 min). Calibration curves were linear in the concentration range of 0.5-100.0 ng/mL for ambroxol and 0.2-20.0 ng/mL for salbutamol, with intra- and inter-run precision (relative standard deviation) <15% and accuracy (relative error) ranging from 97.7 to 112.1% for ambroxol and from 94.5 to 104.1% for salbutamol. The method was successfully applied in a clinical pharmacokinetic study of the compound ambroxol and salbutamol tablets.
Assuntos
Albuterol/sangue , Ambroxol/sangue , Broncodilatadores/sangue , Cromatografia Líquida de Alta Pressão/métodos , Expectorantes/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Feminino , Humanos , Limite de Detecção , Extração Líquido-Líquido/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 µg/kg) and oral (2.0 µg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half-life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses.
Assuntos
Broncodilatadores/farmacocinética , Cavalos/sangue , Procaterol/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Broncodilatadores/sangue , Broncodilatadores/urina , Feminino , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas/veterinária , Masculino , Procaterol/sangue , Procaterol/urinaRESUMO
Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium.
Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacocinética , Sistema Cardiovascular/efeitos dos fármacos , Glicopirrolato/farmacocinética , Antagonistas Muscarínicos/farmacocinética , Derivados da Escopolamina/farmacocinética , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Testes de Provocação Brônquica , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Broncodilatadores/toxicidade , Sistema Cardiovascular/fisiopatologia , Glicopirrolato/administração & dosagem , Glicopirrolato/sangue , Glicopirrolato/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Hipotensão/induzido quimicamente , Hipotensão/fisiopatologia , Masculino , Modelos Biológicos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/sangue , Antagonistas Muscarínicos/toxicidade , Ligação Proteica , Ensaio Radioligante , Ratos Endogâmicos BN , Receptor Muscarínico M2/efeitos dos fármacos , Receptor Muscarínico M2/metabolismo , Medição de Risco , Derivados da Escopolamina/administração & dosagem , Derivados da Escopolamina/sangue , Derivados da Escopolamina/toxicidade , Brometo de TiotrópioRESUMO
AIMS: To establish the dose-response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulized formulation of the long acting muscarinic antagonist glycopyrrolate (EP-101) with a high efficiency nebulizer in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with moderate to severe COPD (GOLD II/III), with reversible lung function, were enrolled into this randomized, double-blind, placebo-controlled, six period crossover study (n = 42). Patients received single doses of EP-101 (12.5-400 µg) and placebo via a high efficiency nebulizer (eFlow® PARI nebulizer), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n = 11). RESULTS: All treatments were well tolerated with similar adverse event rates reported with placebo and at all doses. There were no clinically relevant changes in heart rate, systolic and diastolic blood pressure or in ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5 min. Significant improvements in mean change from baseline FEV1 at 24 h were reported at doses ≥ 50 µg compared with placebo, with a clear dose-response relationship. Mean changes in FEV1 were 0.10 l (95% CI 0.06, 0.14) and 0.12 l (95% CI 0.08, 0.16) for 100 µg and 200 µg, respectively. CONCLUSION: Single doses of EP-101 ranging from 12.5 µg to 400 µg were well tolerated. EP-101 delivered by high efficiency nebulizer device produced a rapid onset of bronchodilatation with clinically meaningful improvements in lung function maintained over a 24 h period at all doses >50 µg.
Assuntos
Broncodilatadores/uso terapêutico , Glicopirrolato/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Desenho de Equipamento , Feminino , Glicopirrolato/administração & dosagem , Glicopirrolato/efeitos adversos , Glicopirrolato/sangue , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/sangue , Nebulizadores e Vaporizadores , Testes de Função Respiratória , Índice de Gravidade de DoençaAssuntos
Coleta de Amostras Sanguíneas/métodos , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Albuterol/sangue , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/sangue , Broncodilatadores/uso terapêutico , Criança , Humanos , Nebulizadores e VaporizadoresRESUMO
OBJECTIVE: Budesonide formoterol (BF) Spiromax® is a breath-actuated dry-powder inhaler designed to deliver similar combinations of budesonide and formoterol as Symbicort® Turbohaler®. We performed two studies to demonstrate pharmacokinetic (PK) equivalence of BF Spiromax with BF Turbohaler. MATERIALS AND METHODS: Two single-center, open-label, randomized, 5-period crossover studies were performed. The first study compared BF Spiromax 160/4.5 µg with BF Turbohaler 200/6 µg, while the second study compared BF Spiromax 320/9 µg with BF Turbohaler 400/12 µg. All treatments were administered with and without charcoal. PK parameters were calculated by measuring plasma drug concentrations from blood samples taken pre-dose and up to 24 hours post-dose. RESULTS: In each study, 90 healthy volunteers were randomized. Bioequivalence of BF Spiromax with BF Turbohaler was demonstrated for budesonide and formoterol (AUC0-t and Cmax (90% confidence intervals of the geometric mean between-device ratios for both parameters were within the predefined range of 0.80-1.25 in both studies)). Equivalence was observed without use of charcoal (overall absorption post-inhalation) and with charcoal (pulmonary absorption). There were no major differences between treatments in tmax for either budesonide or formoterol. All study treatments were well tolerated (one treatment-emergent adverse event (TEAE) in the medium-dose study and four TEAEs in the high-dose study). CONCLUSIONS: These studies indicate that BF Spiromax (±charcoal block) is bioequivalent to BF Turbohaler with respect to the PK parameters assessed. Single doses of BF Spiromax were well tolerated; the overall safety profile of BF Spiromax and BF Turbohaler was similar.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Budesonida/administração & dosagem , Budesonida/farmacocinética , Carvão Vegetal , Inaladores de Pó Seco , Etanolaminas/administração & dosagem , Etanolaminas/farmacocinética , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/sangue , Adulto , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Budesonida/efeitos adversos , Budesonida/sangue , Estudos Cross-Over , Combinação de Medicamentos , Desenho de Equipamento , Etanolaminas/efeitos adversos , Etanolaminas/sangue , Feminino , Fumarato de Formoterol , Glucocorticoides/efeitos adversos , Glucocorticoides/sangue , Voluntários Saudáveis , Humanos , Masculino , Equivalência Terapêutica , Adulto JovemRESUMO
Aminophylline (AMP) is a bronchodilator. The therapeutic and toxic doses are very close. Therefore, therapeutic drug monitoring (TDM) of AMP is essential in clinical practice. Microgels were synthesized by free radical precipitation polymerization. Silver@poly(N-isopropyl acrylamide) (Ag@PNIPAM) hybrid microgels were obtained by loading silver (Ag) nanoparticles into the three-dimensional network of the microgels by in situ reduction. The microgel is a three-dimensional reticular structure with tunable pore size, large specific surface area, and good biocompatibility, which can be used as a sorbent for solid-phase extraction (SPE) of target molecules in complex matrices and as a surface-enhanced Raman spectroscopy (SERS) substrate. We optimized the conditions affecting SERS enhancement, such as silver nitrate (AgNO3) concentration and SPE time, according to the SERS strategy of Ag@PNIPAM hybrid microgels to achieve label-free TDM for trace AMP in human serum. The results showed good linearity between the logarithmic concentration of AMP and its SERS intensity in the range of 1-1.1 × 102â µg/mL, with a correlation coefficient (R2) of 0.9947 and a low detection limit of 0.61â µg/mL. The assay accuracy was demonstrated by spiking experiments, with recoveries ranging from 93.0 to 101.8%. The method is rapid, sensitive, reproducible, requires simple sample pretreatment, and has good potential for use in clinical treatment drug monitoring.
Assuntos
Aminofilina , Limite de Detecção , Microesferas , Prata , Extração em Fase Sólida , Análise Espectral Raman , Aminofilina/sangue , Aminofilina/química , Humanos , Análise Espectral Raman/métodos , Extração em Fase Sólida/métodos , Prata/química , Hidrogéis/química , Nanopartículas Metálicas/química , Resinas Acrílicas/química , Monitoramento de Medicamentos/métodos , Broncodilatadores/sangue , Broncodilatadores/químicaRESUMO
Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.