RESUMEN
Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Peso Corporal , Modelos Biológicos , Humanos , Asma/tratamiento farmacológico , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Adolescente , Antiasmáticos/farmacocinética , Antiasmáticos/administración & dosificación , Antiasmáticos/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Anciano , Niño , Relación Dosis-Respuesta a Droga , Índice de Severidad de la Enfermedad , Inyecciones SubcutáneasRESUMEN
INTRODUCTION: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 µg [medium-strength BDP]; Study 2: 200/6/12.5 µg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %. RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies. CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.
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Propelentes de Aerosoles , Beclometasona , Estudios Cruzados , Combinación de Medicamentos , Fumarato de Formoterol , Glicopirrolato , Inhaladores de Dosis Medida , Beclometasona/farmacocinética , Beclometasona/administración & dosificación , Humanos , Fumarato de Formoterol/farmacocinética , Fumarato de Formoterol/administración & dosificación , Masculino , Glicopirrolato/farmacocinética , Glicopirrolato/administración & dosificación , Administración por Inhalación , Adulto , Método Doble Ciego , Femenino , Persona de Mediana Edad , Adulto Joven , Área Bajo la Curva , Equivalencia Terapéutica , Broncodilatadores/farmacocinética , Broncodilatadores/administración & dosificación , Antiasmáticos/farmacocinética , Antiasmáticos/administración & dosificación , FluorocarburosAsunto(s)
Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Humanos , Asma/tratamiento farmacológico , Antiasmáticos/uso terapéutico , Antiasmáticos/farmacocinética , Niño , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Eosinofilia , Eosinófilos/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
INTRODUCTION: Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules. METHODS: Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated. RESULTS: Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose-response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4-6 h (short), 14-16 h (medium), 25-40 h (long), or > 80 h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action. CONCLUSION: In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma.
Patients with asthma often rely on inhaled corticosteroids to manage their symptoms by controlling lung inflammation. Inhaled corticosteroids can be used at low, medium, or high doses; however, the effectiveness, safety, and how long the effects last for a particular inhaled corticosteroid molecule are not considered when choosing them. This study investigated the safety and efficacy of different inhaled corticosteroid molecules. Leveraging published data on the mode of anti-inflammatory action and the rates these molecules are absorbed and eliminated from the body, we estimated their effectiveness and safety profiles, including duration of action in the lungs and systemic exposure levels. Some inhaled corticosteroid molecules such as fluticasone furoate, fluticasone propionate, and ciclesonide were found to exhibit high anti-inflammatory effectiveness in the lungs with minimal systemic exposure, contrasting the perceived similarities among currently used drug molecules. Anti-inflammatory duration of the unwanted systemic effect in the rest of the body was unique for each inhaled corticosteroid molecule. Notably, even the lowest doses of most inhaled corticosteroids were found to be effective in the lungs when taken as prescribed, supporting previous observations that clinical benefits are mostly realized at lower doses. Furthermore, estimated post dose durations of effectiveness for different inhaled corticosteroid molecules varied widely among different molecules, with some lasting a few hours and others lasting more than 80 h, suggesting significant differences in their duration of action. Overall, these findings demonstrate the potential advantage of using longer-acting inhaled corticosteroids, particularly for patients with asthma who may face challenges in adhering to prescribed regimens.
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Corticoesteroides , Asma , Relación Dosis-Respuesta a Droga , Humanos , Administración por Inhalación , Asma/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Corticoesteroides/farmacocinética , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacocinética , Receptores de Glucocorticoides/efectos de los fármacos , Resultado del Tratamiento , Fluticasona/administración & dosificaciónRESUMEN
Omalizumab is widely used in clinical practice; however, knowledge gaps in the dosage of omalizumab for children aged 2-6 years with moderate-to-severe persistent allergic asthma have been identified. The aim of this study was to explore dosing regimens for moderately-to-severely allergic pediatric patients aged 2-6 years. The physiologically-based pharmacokinetic (PBPK) model of omalizumab was developed and verified in adult patients, extrapolated to pediatric patients, and simulated for omalizumab by adding two observation chambers (free IgE and total IgE). The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax ) were between 0.5 and 2.0, and the average folding error and the absolute average folding error values for all concentration-time data points were 1.09 and 1.48, respectively. The PBPK model combined with pharmacokinetic/pharmacodynamic analysis of omalizumab demonstrated that both the model-derived dose and the original dose could control the average free IgE of 2-6-year-old children with moderate-to-severe allergic asthma below 25 ng/mL, and some of the model-derived doses were lower. This conclusion provides a basis for the selection of dosage in clinical practice reference.
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Antiasmáticos , Asma , Adulto , Niño , Humanos , Omalizumab/farmacocinética , Antiasmáticos/farmacocinética , Inmunoglobulina E/uso terapéutico , Asma/tratamiento farmacológico , Simulación por ComputadorRESUMEN
The single-inhaler extrafine formulation triple combination beclometasone dipropionate (BDP), formoterol fumarate (FF) plus glycopyrronium bromide (GB) is available for asthma management in adults. Its use in adolescents has not yet been evaluated. This study investigated the pharmacokinetic profile of BDP/FF/GB in adults and adolescents, with the aim of ruling out higher plasma exposure in adolescents compared to adults. In this open-label, non-randomized study, patients with asthma aged 12-17 (adolescents) and 18-64 years (adults) self-administered a single dose of BDP/FF/GB 400/24/50 µg via pressurized metered-dose inhaler (pMDI). The primary objective was to rule out higher systemic exposure to beclometasone 17-monopropionate (B17MP; active metabolite of BDP), formoterol, and GB in terms of the area under the plasma concentration-time curve from 0 to the last quantifiable concentration (AUC0-t ) in adolescents versus adults. A total of 40 adolescents and 40 adults entered the study (mean age of 14.8 and 43.6 years, respectively). The primary objective (AUC0-t ) was met, with the upper 90% confidence interval of the geometric mean ratio between adolescents and adults <125% for B17MP (point estimate 79.28 [90% CI 71.19; 88.29]), formoterol (88.68 [77.71; 101.20]) and GB (85.49 [72.96; 100.16]). All secondary pharmacokinetic endpoints supported the primary, with pharmacodynamic (safety) and tolerability results similar in the two populations. In conclusion, systemic exposure to extrafine BDP/FF/GB pMDI in adolescents was not higher than that in adults. Furthermore, there were no safety or tolerability signals to warrant a reduction in the dose of BDP/FF/GB for adolescents with asthma.
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Antiasmáticos , Asma , Adolescente , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Asma/tratamiento farmacológico , Beclometasona/efectos adversos , Beclometasona/farmacocinética , Niño , Combinación de Medicamentos , Fumarato de Formoterol/efectos adversos , Fumarato de Formoterol/farmacocinética , Glicopirrolato/efectos adversos , Glicopirrolato/farmacocinética , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: This is the first-in-human study to evaluate the pharmacokinetics, safety, and tolerability of TQC3564 (a novel CRTh2 receptor antagonist) in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: This project was a phase Ia clinical study of TQC3564 as a single-ascending dose (SAD) (25 to 1200 mg) and a multiple-ascending dose (MAD) (100 or 500 mg, QD) as well as a two-period crossover food-effect study (300 mg). RESULTS: In the SAD and MAD study, TQC3564 were found to be safe and well tolerated, without dose-dependent adverse events (AEs), and all AEs were mild or moderate in severity. In the SAD study, the median tmax of TQC3564 was 2.5-4.5 h, and t1/2 was 8.13-35.7 h. Exposure was increased after food intake. The MAD study results showed that steady-state was achieved on day 4. Moreover, no apparent TQC3564 plasma accumulation was detected on day 7. CONCLUSIONS: In healthy subjects, TQC3564 at a single dose of 25-1200 mg or 100-500 mg at multiple doses (QD) was safe and tolerable with acceptable PK profiles, indicating that TQC3564 has potential as a therapeutic option for asthma. (This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20192397.).
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Antiasmáticos , Voluntarios Sanos , Administración Oral , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Área Bajo la Curva , China , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Receptores InmunológicosRESUMEN
BACKGROUND: MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells. OBJECTIVE: The objective of this study is to identify and quantify MIDD0301 metabolites in vitro and in vivo and determine the pharmacokinetics of oral, IP, and IV administered MIDD0301. METHODS: In vitro conversion of MIDD0301 was performed using liver and kidney microsomes/S9 fractions followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A LC-MS/MS method was developed using synthesized standards to quantify MIDD0301 and its metabolites in urine and feces. Blood, lung, and brain were harvested from animals that received MIDD0301 by oral, IP, and IV administration, followed by LCMS/ MS quantification. Imaging mass spectrometry was used to demonstrate the presence of MIDD0301 in the lung after oral administration. RESULTS: MIDD0301 is stable in the presence of liver and kidney microsomes and S9 fractions for at least two hours. MIDD0301 undergoes conversion to the corresponding glucuronide and glucoside in the presence of conjugating cofactors. For IP and IV administration, unconjugated MIDD0301 together with significant amounts of MIDD0301 glucoside and MIDD0301 taurine were found in urine and feces. Less conjugation was observed following oral administration, with MIDD0301 glucuronide being the main metabolite. Pharmacokinetic quantification of MIDD0301 in blood, lung, and brain showed very low levels of MIDD0301 in the brain after oral, IV, or IP administration. The drug half-life in these tissues ranged between 4-6 hours for IP and oral and 1-2 hours for IV administration. Imaging mass spectrometry demonstrated that orally administered MIDD0301 distributes uniformly in the lung parenchyma. CONCLUSION: MIDD0301 undergoes no phase I and moderate phase II metabolism.
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Antiasmáticos/farmacocinética , Azepinas/farmacocinética , Imidazoles/farmacocinética , Riñón/metabolismo , Microsomas Hepáticos/metabolismo , Administración Intravenosa , Administración Oral , Animales , Antiasmáticos/administración & dosificación , Azepinas/administración & dosificación , Cromatografía Liquida , Perros , Femenino , Humanos , Imidazoles/administración & dosificación , Inyecciones Intraperitoneales , Pulmón/metabolismo , Ratones , Microsomas/metabolismo , Ratas , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
PURPOSE: Traditionally, α-lactose monohydrate is the carrier of choice in dry powder inhaler (DPI) formulations. Nonetheless, other sugars, such as D-mannitol, have emerged as potential alternatives. Herein, we explored different particle engineering processes to produce D-mannitol carriers for inhaled delivery. METHODS: Wet-sieving and spray-congealing were employed as innovative techniques to evaluate the impact of engineering on the particle properties of D-mannitol. To that end, the resulting powders were characterized concerning their solid-state, micromeritics and flowability. Afterwards, the engineered carrier particles were blended with inhalable size beclomethasone dipropionate to form low dose (1 wt%) DPI formulations. The in vitro aerosolization performance was evaluated using the NEXThaler®, a reservoir multi-dose device. RESULTS: Wet-sieving generated D-mannitol particles with a narrow particle size distribution and spray-congealing free-flowing spherical particles. The more uniform pumice particles with deep voids and clefts of wet-sieved D-mannitol (Pearl300_WS) were beneficial to drug aerosolization, only when used in combination with a ternary agent (10 wt% of 'Preblend'). When compared to the starting material, the spray-congealed D-mannitol has shown to be promising in terms of the relative increase of the fine particle fraction of the drug (around 100%), when used without the addition of ternary agents. CONCLUSIONS: The wet-sieving process and the related aerosolization performance are strongly dependent on the topography and structure of the starting material. Spray-congealing, has shown to be a potential process for generating smooth spherical particles of D-mannitol that enhance the in vitro aerosolization performance in binary blends of the carrier with a low drug dose.
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Ingeniería Química/métodos , Química Farmacéutica/métodos , Portadores de Fármacos/síntesis química , Inhaladores de Polvo Seco/métodos , Nanopartículas/química , Administración por Inhalación , Antiasmáticos/administración & dosificación , Antiasmáticos/síntesis química , Antiasmáticos/farmacocinética , Beclometasona/administración & dosificación , Beclometasona/síntesis química , Beclometasona/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Manitol/administración & dosificación , Manitol/síntesis química , Manitol/farmacocinética , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.
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Asma/tratamiento farmacológico , Glicopirrolato/análogos & derivados , Indanos/farmacocinética , Modelos Biológicos , Furoato de Mometasona/farmacocinética , Quinolonas/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacocinética , Niño , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Glicopirrolato/administración & dosificación , Glicopirrolato/farmacocinética , Humanos , Indanos/administración & dosificación , Masculino , Persona de Mediana Edad , Furoato de Mometasona/administración & dosificación , Nebulizadores y Vaporizadores , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
BACKGROUND: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVES: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured â¼30 patients who were eosinophil-high (≥300 cells/µL) and â¼95 patients who were eosinophil-low (<300 cells/µL) per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. CONCLUSIONS: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.
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Antiasmáticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Asma/inmunología , Progresión de la Enfermedad , Método Doble Ciego , Eosinófilos/inmunología , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/antagonistas & inhibidores , Interleucina-33/antagonistas & inhibidores , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. OBJECTIVE: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. METHODS: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. RESULTS: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. CONCLUSIONS: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Óxido Nítrico/metabolismo , Adolescente , Adulto , Antiasmáticos/sangre , Antiasmáticos/farmacocinética , Antiasmáticos/farmacología , Asma/metabolismo , Método Doble Ciego , Espiración , Femenino , Humanos , Inhibidores de las Cinasas Janus/sangre , Inhibidores de las Cinasas Janus/farmacocinética , Inhibidores de las Cinasas Janus/farmacología , Masculino , Adulto JovenRESUMEN
BACKGROUND: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. METHODS: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 µg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 µg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. RESULTS: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. CONCLUSION: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.
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Antiasmáticos/farmacocinética , Glicopirrolato/farmacocinética , Indanos/farmacocinética , Furoato de Mometasona/farmacocinética , Quinolonas/farmacocinética , Administración por Inhalación , Adulto , Antiasmáticos/administración & dosificación , Pueblo Asiatico , Estudios Cruzados , Combinación de Medicamentos , Femenino , Glicopirrolato/administración & dosificación , Voluntarios Sanos , Humanos , Indanos/administración & dosificación , Masculino , Furoato de Mometasona/administración & dosificación , Quinolonas/administración & dosificación , Población Blanca , Adulto JovenRESUMEN
Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti-inflammatory properties, not all inflammatory pathways are responsive to systemic corticosteroids, necessitating hospital admission for further management. Cysteinyl leukotrienes (LTs) are proinflammatory mediators that play an important role in systemic corticosteroids non-responsiveness. Montelukast is a potent LT-receptor antagonist, and an intravenous preparation caused rapid, sustained improvement of acute asthma exacerbations in adults. We hypothesized that a 30-mg dose of oral montelukast achieves peak plasma concentrations (Cmax ), comparable to the intravenous preparation (1700 ng/mL) and would be well tolerated in 15 children aged 5 to 12 years with acute asthma exacerbations. After administration of montelukast chewable tablets, blood samples were collected at 0, 15, 30, 45, 60, 120, 180, and 240 minutes. Plasma was separated and frozen at -80°C until analysis for montelukast concentration using liquid chromatography- tandem mass spectrometry. Median time to Cmax (tmax ) was 3.0 hours. Six participants (40%) achieved Cmax of 1700 ng/mL or higher. However, there was high interindividual variability in peak plasma concentration (median Cmax of 1378 ng/mL; range, 16-4895 ng/mL). No participant had side effects or adverse events. Plasma concentrations from this pilot study support the design of a weight-based dose-finding study aimed at selecting an optimal dose for future clinical trials to assess the efficacy of high-dose oral montelukast in children with moderate to severe asthma exacerbations.
Asunto(s)
Acetatos/administración & dosificación , Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Ciclopropanos/administración & dosificación , Antagonistas de Leucotrieno/administración & dosificación , Quinolinas/administración & dosificación , Sulfuros/administración & dosificación , Acetatos/efectos adversos , Acetatos/farmacocinética , Administración Oral , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Asma/fisiopatología , Peso Corporal , Niño , Preescolar , Cromatografía Liquida , Ciclopropanos/efectos adversos , Ciclopropanos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Antagonistas de Leucotrieno/efectos adversos , Antagonistas de Leucotrieno/farmacocinética , Masculino , Gravedad del Paciente , Proyectos Piloto , Estudios Prospectivos , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Sulfuros/efectos adversos , Sulfuros/farmacocinética , Comprimidos , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
OBJECTIVE: We compared the pharmacokinetic exposure following a single subcutaneous dose of benralizumab 30 mg using either autoinjectors (AI) or accessorized prefilled syringes (APFS). APFS and AI functionality and reliability for at-home benralizumab delivery have been demonstrated in the GREGALE and GRECO studies, respectively. METHODS: In the open-label AMES study (NCT02968914), 180 healthy adult men and women were randomized to one of two device (AI or APFS) and three injection site (upper arm, abdomen, or thigh) combinations. Randomization was stratified by weight (<70 kg, 70-84.9 kg, and ≥85 kg). Blood eosinophil counts were measured on Days 1, 8, 29, and 57. RESULTS: Benralizumab pharmacokinetic exposure was similar between AI and APFS. Geometric mean ratios (AI/APFS) (90% CI) were 92.8% (87.4-98.6) and 94.5% (88.2-101.2) for two area under the concentrationâtime curve measurements (AUClast and AUCinf). Benralizumab exposure was approximately 15-30% greater for thigh vs. abdomen or upper arm administration. Exposure was slightly greater for APFS vs. AI regardless of injection site or weight class. These differences were unlikely to be clinically relevant, as eosinophil depletion was achieved consistently with both devices at all injection sites. No device malfunctions were reported. No new or unexpected safety findings were observed. CONCLUSION: Benralizumab pharmacokinetic exposure was similar between AI and APFS, with consistent blood eosinophil count depletion observed with both devices. These results support benralizumab administration with either AI or APFS, providing patients and physicians increased choice, flexibility, and convenience for potential at-home delivery.
Asunto(s)
Antiasmáticos/farmacocinética , Anticuerpos Monoclonales Humanizados/farmacocinética , Jeringas , Adulto , Antiasmáticos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Humanos , Inyecciones Subcutáneas/instrumentación , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Fexofenadine hydrochloride is an antihistamine agent used for the treatment of allergic disorders like rhinitis. It is a second generation antihistamine. Montelukast sodium is an anti-asthmatic agent and leukotriene receptor antagonist used in the treatment of respiratory disorders. This article exemplifies the reported analytical methods like electrometric methods, ultraviolet spectroscopy, mass spectroscopy, thin layer chromatography, high performance liquid chromatography, high performance thin layer chromatography and tandem spectroscopy for determination of fexofenadine HCl and montelukast sodium in dosage form and in biological matrices. This review covers almost all the analytical methods for fexofenadine hydrochloride and montelukast sodium form 1968-2018 years. Complete analytical validation parameters reported are discussed in this review for both analytes. Among various analytical methods, HPLC and UV-visible spectrophotometry were found to be the most extensively used methods by the researchers.
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Acetatos/análisis , Antialérgicos/análisis , Técnicas de Química Analítica/métodos , Ciclopropanos/análisis , Monitoreo de Drogas/métodos , Antagonistas de Leucotrieno/análisis , Quinolinas/análisis , Sulfuros/análisis , Terfenadina/análogos & derivados , Acetatos/farmacocinética , Animales , Antialérgicos/farmacocinética , Antiasmáticos/análisis , Antiasmáticos/farmacocinética , Técnicas de Química Analítica/instrumentación , Ciclopropanos/farmacocinética , Monitoreo de Drogas/instrumentación , Antagonistas de los Receptores Histamínicos H1 no Sedantes/análisis , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacocinética , Humanos , Antagonistas de Leucotrieno/farmacocinética , Quinolinas/farmacocinética , Sulfuros/farmacocinética , Terfenadina/análisis , Terfenadina/farmacocinéticaRESUMEN
SRS27, an andrographolide analogue, had been proven to have therapeutic properties at a dose of 3 mg/kg in both in vitro and in vivo asthma models of our previous study. The present study focuses on the pharmacokinetic and toxicity profile of this compound to provide further evidence for the development of this compound as an anti-asthma agent. A simple pharmacokinetic study was performed in female BALB/c mice to measure blood plasma concentration of the compound at therapeutic dose. At a single dose of 3 mg/kg, SRS27 had a relatively short half-life but was able to achieve a concentration range of 13-19 µM that is related to its in vitro bioactivities. With regard to toxicity profile, SRS27 appears to be safe, as no histopathological changes were observed in the liver, kidneys and ovaries of SRS27-treated female BALB/c mice. In addition, there was no significant change in the mean body weight and organ weight of the animals in the SRS27-treated groups compared with the vehicle-treated control group at the end of the treatment. This fully supports the absence of any significant changes in peripheral blood leukocyte counts of SRS27-treated mice. Rewardingly, this acute toxicity study also revealed that SRS27 has a wide therapeutic window as no toxicity symptoms were detected with a dose up to 60 mg/kg daily when tested for 14 days. These results provide strong justification for further investigation of SRS27 as a potential new anti-asthma agent.
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Antiasmáticos/farmacocinética , Antiasmáticos/toxicidad , Diterpenos/farmacocinética , Diterpenos/toxicidad , Lactonas/farmacocinética , Lactonas/toxicidad , Animales , Antiasmáticos/sangre , Disponibilidad Biológica , Diterpenos/sangre , Femenino , Riñón/anatomía & histología , Riñón/efectos de los fármacos , Lactonas/sangre , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Pulmón/anatomía & histología , Pulmón/efectos de los fármacos , Ratones Endogámicos BALB C , Ovario/anatomía & histología , Ovario/efectos de los fármacosRESUMEN
BACKGROUND/OBJECTIVE: To study the therapeutic potential of Antileukotriene drug- Camellia sinensis extract co-formulation on histamine induced asthma in guinea pigs. METHODS: SRSD of Montelukast sodium was prepared by the solvent evaporation method. Lyophilized aqueous extract of Camellia sinensis leaves and SRSD mixture was filled in capsule and the capsule shell was coated to achieve initial release lag time. In vitro and pharmacokinetic study of capsules was performed and compared with commercial tablets. A further role of green tea, as an antioxidant adjunct for asthma management, has been analyzed by lung histology, mast cell count and oxidative stress assay in the serum of control and experimental animals. RESULTS: The drug release from the commercial tablet was immediate and rapid, but capsule has shown an initial 3.5 hr lag time followed by sustained action up to 8 hr. Pharmacokinetic results show that studied formulations are bioequivalent with respect to Cmax and AUC, while rest parameters showed asignificant difference. Mast cells count in lung tissue were increased (p<0.001) in the experimental group along with glycoprotein deposition in asthmatic bronchioles. Levels of SOD and GPX were decreased (p<0.05) while CAT was increased (p<0.04) in the asthma group in comparison to control. CONCLUSION: In the experimental animal model, co-formulation was effective in modulating allergic inflammation and contributing to better control of the inflammatory response. Our findings suggest that Camellia sinensis leaves extract may be used as an adjunct for future improvements in asthma treatment and prevention.
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Asma/tratamiento farmacológico , Camellia sinensis/química , Antagonistas de Leucotrieno/farmacología , Extractos Vegetales/farmacología , Animales , Antiasmáticos/aislamiento & purificación , Antiasmáticos/farmacocinética , Antiasmáticos/farmacología , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Área Bajo la Curva , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Liberación de Fármacos , Cobayas , Histamina/inmunología , Inflamación/tratamiento farmacológico , Inflamación/patología , Antagonistas de Leucotrieno/aislamiento & purificación , Antagonistas de Leucotrieno/farmacocinética , Masculino , Mastocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacocinética , Hojas de la PlantaRESUMEN
PURPOSE: Tezepelumab is an anti-thymic stromal lymphopoietin monoclonal antibody therapeutic in development for patients with severe, uncontrolled asthma. In ongoing Phase III studies, tezepelumab is administered via subcutaneous (SC) injections using a vial-and-syringe (V-S). This study compared the pharmacokinetic (PK) parameters, safety, and tolerability of tezepelumab administered subcutaneously via V-S versus via an accessorized prefilled syringe (APFS) or autoinjector (AI). METHODS: This single-center, randomized, open-label, parallel-group study was conducted in healthy volunteers aged 18-65 years. Participants, stratified according to weight (50 to <70 kg, 70 to <80 kg, or 80-90 kg), were randomized evenly to 9 groups representing injections to the abdomen, thigh, or upper arm via V-S, APFS, or AI. Tezepelumab PK parameters over 113 days were evaluated after a single 210-mg SC dose. The primary end points were comparison of Cmax and AUC0-∞ between device groups. Further PK parameters, immunogenicity, safety (including injection site reactions [ISRs] and injection site pain [visual analog scale]) were also assessed. FINDINGS: A total of 315 adults were randomized to treatment. Geometric mean ratios for comparisons between device groups of Cmax, AUC0-∞, and AUC0-last were close to 1, with 90% CIs all within the range of 0.8-1.25, meeting bioequivalence criteria. PK variables were also similar between devices across injection sites and weight categories. Across devices, thigh injection resulted in slightly higher exposure than upper arm injection, and abdomen injection resulted in exposure similar to or slightly lower than thigh injection; however, these differences were not clinically meaningful. Treatment-emergent anti-tezepelumab antibodies were present in 3 (2.9%), 1 (1.0%), and 0 participants in the V-S, APFS, and AI groups, respectively. Treatment-related adverse events were reported in 15.0% of participants overall (V-S, 10.7%; APFS, 18.1%; AI, 16.0%), including ISRs in 1 (1.0%), 3 (2.9%), and 3 (2.8%) participants in the V-S, APFS, and AI groups. Median visual analog scale pain score (0-100 mm scale) was 2 mm immediately after injection and was 0 mm at 30 min for all groups. IMPLICATIONS: Tezepelumab PK parameters after a single 210-mg SC dose were comparable when administered via V-S, APFS, or AI. In all groups, immunogenicity rate and injection site pain were low, and ISRs were uncommon. These findings support administration of tezepelumab via APFS or AI, in addition to V-S, providing patients and physicians with greater choice and the potential convenience of at-home use. ClinicalTrials.gov identifier: NCT03989544.
Asunto(s)
Antiasmáticos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Sistemas de Liberación de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Dimensión del Dolor , JeringasRESUMEN
Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab significantly reduced exacerbations in adults with severe, uncontrolled asthma. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling to guide tezepelumab dose selection for phase 3 trials in patients with severe asthma. PK data from 7 clinical studies were used to develop a population PK model. Population PK-PD models were developed to characterize the relationship between tezepelumab PK and asthma exacerbation rate (AER) and fractional exhaled nitric oxide (FeNO) levels (using phase 2b PD data only). Tezepelumab PK were well described by a 2-compartment model with first-order absorption; PK parameter estimates were consistent with those of other immunoglobulin G2 antibodies. PK-PD models predicted that subcutaneous dosing at 210 mg every 4 weeks was associated with ≈90% of the maximum drug effect of tezepelumab on AER and FeNO; further dose increases were not expected to result in additional, clinically meaningful treatment benefit. No clinically significant covariates of treatment effects on AER and FeNO were identified. Population PK simulations, exposure-response relationships and safety profiles of tezepelumab at doses up to 280 mg every 2 weeks suggested that no dose adjustment based on body weight or for adolescents was required. These results support the selection of 210 mg every 4 weeks subcutaneously as the dose for phase 3 studies of tezepelumab in adults and adolescents with severe asthma.