Exclusão do Xinafoato de Salmeterol aerossol bucal 50 mcg para tratamento da Asma e da Doença Pulmonar Obstrutiva Crônica / Exclusion of Salmeterol Xinafoate Oral Aerosol 50 mcg for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

CONTEXTO: A asma é uma doença heterogênea caracterizada por inflamação crônica das vias aéreas, enquanto a DPOC possui caráter não totalmente reversível caracterizada pela limitação crônica ao fluxo aéreo frequentemente associada a uma resposta inflamatória crônica das vias aéreas e do tecido pulmonar. O tratamento da asma e do DPOC visa melhorar a qualidade de vida do paciente por meio do controle dos sintomas e melhora ou estabilização da função pulmonar, além da diminuição das exacerbações na DPOC. O xinafoato de salmeterol, ß2-agonista de longa duração (LABA), é um dos medicamentos utilizado no tratamento dessas enfermidades, todavia sua forma farmacêutica de aerossol bucal 50 mcg não possui registro válido na ANVISA. Existem ainda outros medicamentos da mesma classe LABA disponibilizados no âmbito do SUS, como formoterol e formoterol + budesonida (cápsula ou pó inalante). Sendo assim, a exclusão do salmeterol aerossol bucal 50 mcg não traria prejuízo à população devido à existência de alternativas terapêuticas para essas condições no SUS. TECNOLOGIA: Xinafoato de salmeterol aerossol bucal 50 mcg. JUSTIFICATIVA DA EXCLUSÃO: Ausência de registro válido do xinafoato de salmeterol 50 mcg aerossol bucal na ANVISA. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A matéria teve sua apreciação inicial na 94ª reunião ordinária da Conitec, no dia 03 de fevereiro de 2021. O Plenário deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à exclusão do salmeterol aerossol bucal para o tratamento da asma e do DPOC, considerando o cancelamento do registro em 2017. CONSULTA PÚBLICA: A Consulta Pública nº 08 foi realizada entre os dias 18/02/2021 e 09/03/2021. Foram recebidas 26 contribuições, sendo seis pelo formulário para contribuições técnico-científicas e 20 pelo formulário para contribuições sobre experiência ou opinião. Dentre as contribuições técnico-científicas, quatro (67%) foram a favor e duas (33%) discordaram da recomendação preliminar da Conitec; dentre as de experiência e opinião, seis (30%) concordaram, três (15%) não concordaram e nem discordaram e onze (55%) discordaram. Embora tenham sido apresentadas contribuições contra a exclusão do salmeterol aerossol, ressalta-se que ele não apresenta registro junto à Anvisa. O SUS disponibiliza outros tratamentos para o controle das condições clínicas, de modo que os pacientes não ficariam desassistidos. Nenhuma das contribuições apresentou novos estudos ou documentos que pudessem agregar novas evidências a esse relatório. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec presentes na 96ª Reunião Ordinária, recomendaram, por unanimidade, a exclusão do salmeterol na apresentação de aerossol bucal (50mcg). Embora tenham sido apresentados relatos positivos acerca deste medicamento, seu registro foi cancelado e deferido pela Anvisa em 2017. Foi assinado o Registro de Deliberação nº 601/2021. DECISÃO: excluir o xinafoato de salmeterol aerossol bucal 50 mcg para tratamento da Asma e da Doença Pulmonar Obstrutiva Crônica (DPOC), conforme Portaria nº 16, publicada no Diário Oficial da União nº 79, seção 1, página 328/329, em 29 de abril de 2021.

Pharmacokinetics of salmeterol and its main metabolite α-hydroxysalmeterol after acute and chronic dry powder inhalation in exercising endurance-trained men: Implications for doping control.

As of 2020, use of beta2 -agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 µg in 24 h. In contrast to beta2 -agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by ultra-high-performance liquid chromatography-tandem mass spectrometry [UHPLC-MS/MS]) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 µg) and high therapeutic (200 µg) doses, and after seven consecutive days of therapeutic inhalation (200 µg × day-1 ) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean ± SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0 ± 1.6, 2.1 ± 1.5, and 2.2 ± 1.1 ng × ml-1 for 400 µg, 200 µg, and seven consecutive days of 200 µg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6 ± 6.1, 5.7 ± 4.6, and 6.5 ± 2.6 ng × ml-1 . Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng × ml-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 µg) from supratherapeutic use (400 µg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

Microencapsulation of Fluticasone Propionate and Salmeterol Xinafoate in Modified Chitosan Microparticles for Release Optimization.

Chitosan (CS) is a natural polysaccharide, widely studied in the past due to its unique properties such as biocompatibility, biodegradability and non-toxicity. Chemical modification of CS is an effective pathway to prepare new matrices with additional functional groups and improved properties, such as increment of hydrophilicity and swelling rate, for drug delivery purposes. In the present study, four derivatives of CS with trans-aconitic acid (t-Acon), succinic anhydride (Succ), 2-hydroxyethyl acrylate (2-HEA) and acrylic acid (AA) were prepared, and their successful grafting was confirmed by FTIR and 1H-NMR spectroscopies. Neat chitosan and its grafted derivatives were fabricated for the encapsulation of fluticasone propionate (FLU) and salmeterol xinafoate (SX) drugs, used for chronic obstructive pulmonary disease (COPD), via the ionotropic gelation technique. Scanning electron microscopy (SEM) micrographs demonstrated that round-shaped microparticles (MPs) were effectively prepared with average sizes ranging between 0.4 and 2.2 µm, as were measured by dynamic light scattering (DLS), while zeta potential verified in all cases their positive charged surface. FTIR spectroscopy showed that some interactions take place between the drugs and the polymeric matrices, while X-ray diffraction (XRD) patterns exhibited that both drugs were encapsulated in MPs' interior with a lower degree of crystallinity than the neat drugs. In vitro release studies of FLU and SX exposed a great amelioration in the drugs' dissolution profile from all modified CS's MPs, in comparison to those of neat drugs. The latter fact is attributed to the reduction in crystallinity of the active substances in the MPs' interior.

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging.

Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI). Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d3, salbutamol-d3, and FP-d3 were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention. Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs. Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.

Effect of particle deposition density of dry powders on the results produced by an in vitro test system simulating dissolution- and absorption rates in the lungs.

The surface area of the air/liquid interface in the lungs is substantial, so deposited doses of aerosol medicines per interface surface area when administered via the inhalation route is always quite low. However, in most in vitro systems used for dissolution testing of dry powder inhalables, the dose per surface area is generally much higher. The aim of this study was to investigate in one in vitro lung dissolution system, the DissolvIt, the manner in which the deposited dose per test surface area of drug particles influences the simulated dissolution- and absorption rate. Here we used the dissolution test method DissolvIt to investigate the influence on dissolution behavior by varying the deposited surface density of tested drugs. Dry powders of three different active pharmaceutical ingredients with different solubilities were used; salmeterol, budesonide and fluticasone propionate. It was found that by varying the dose density from 0.23 to 29 µg/cm2 the dissolution- and absorption rate of test particles was affected for all three substances, with decreasing relative dissolution rates above certain dose limits. The effect was much more prominent with the least soluble fluticasone propionate. In contrast, in a real lung it has been shown that a tenfold increase of the even less soluble fluticasone furoate did not affect the pulmonary dissolution- and absorption as measured in the ex vivo isolated perfused rat lung. This indicates that the deposited particle dose on the test surface used must be carefully considered in all in vitro dissolution testing apparatuses used for inhalation drugs, especially when aiming for in vitro-in vivo correlations. Conclusive data show that in the DissolvIt system consistent normalized dissolution- and absorption data can be obtained if the deposition density of test substance are kept below 1 µg/cm2 and the variability between the initial drug doses is smaller than 10-15% expressed as standard deviation.

Human Stimulus Factor Is a Promising Peptide for Delivery of Therapeutics.

Fluticasone propionate uptake in the presence of a proprietary cell-penetrating peptide (human stimulus factor, [HSF]) based on the N-terminal domain of lactoferrin was studied, alone and in combination with salmeterol, using an air interface Calu-3 epithelial model. The HSF enhanced uptake and transport of fluticasone propionate across the epithelial barrier when alone and in presence of salmeterol. This was attributed to transcellular-mediated uptake. This HSF is a promising peptide for delivery of therapeutics where enhanced epithelial penetrating is required.

Bioequivalence of fluticasone propionate and salmeterol (FS) given by the FS Spiromax® and Seretide Accuhaler® systems
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OBJECTIVE: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 µg and Seretide Accuhaler 50/500 µg inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed. MATERIALS AND METHODS: In two single-center, open-label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose. Bioequivalence was established if the 90% confidence intervals for the geometric mean ratios of the area under the plasma drug concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t) and the maximum observed plasma concentration (Cmax) for the comparison of both FP and SAL were within 0.80 - 1.25. RESULTS: In study 1, in subjects administered FS Spiromax, the mean (standard deviation (SD)) FP AUC0-t and Cmax were 1,622.64 (419.44) pg×h/mL and 151.36 (40.37) pg/mL, respectively, vs. 1,487.52 (341.25) pg×h/mL and 137.57 (33.64) pg/mL with Seretide Accuhaler. Mean (SD) SAL AUC0-t and Cmax with FS Spiromax were 408.42 (155.40) pg×h/mL and 269.48 (105.74) pg/mL, respectively, vs. 401.79 (125.32) pg×h/mL and 265.66 (87.28) pg/mL with Seretide Accuhaler. Comparable data were seen in study 2 with charcoal block. Bioequivalence of FS Spiromax with Seretide Accuhaler was observed both without and with charcoal block for FP and SAL for both AUC0-t and Cmax. Both study treatments were well tolerated, with a similar incidence of adverse events reported with the single use of FS Spiromax (23% study 1, 16% study 2) and Seretide Accuhaler (22%, 15%). CONCLUSION: FS Spiromax 500/50 µg (± charcoal block) was bioequivalent to Seretide Accuhaler 50/500µg.
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Pharmacokinetics of Salmeterol and Fluticasone Propionate Delivered in Combination via Easyhaler and Diskus Dry Powder Inhalers in Healthy Subjects.

BACKGROUND: Easyhaler® dry powder inhaler (DPI) containing salmeterol and fluticasone propionate was developed for the treatment of asthma and chronic obstructive pulmonary disease. Three different Salmeterol/fluticasone Easyhaler test products (Orion Pharma, Finland) were compared against the reference product Seretide® Diskus® DPI (GlaxoSmithKline, United Kingdom) to study whether any of the test products are bioequivalent with the reference. METHODS: Open and randomized pharmacokinetic four-period crossover study on 65 healthy volunteers was performed in a single center to compare the lung deposition and total systemic exposure of salmeterol and fluticasone propionate after administration of single doses (two inhalations of 50/500 µg/inhalation strength) in fasting conditions. Blood samples were drawn before dosing and at frequent time points between 2 minutes and 34 hours after dosing for determination of drug concentrations. The primary variables for total systemic exposure and lung deposition of fluticasone propionate were maximum concentration of the concentration-time curve (Cmax) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUCt). For salmeterol, the primary variables for total systemic exposure were Cmax and AUCt and for lung deposition Cmax and AUC up to 30 minutes after study treatment administration (AUC30min). RESULTS: One of the Easyhaler test products met all the criteria for bioequivalence with the reference. The 96.7% confidence intervals (CIs) for the test/reference ratios of fluticasone propionate Cmax and AUCt were 0.9901-1.1336 and 0.9448-1.0542, respectively. Ninety percent CIs for salmeterol Cmax, AUC30min, and AUCt ratios were 1.0567-1.2012, 1.0989-1.2255, and 1.0769-1.1829, respectively. Median salmeterol time to maximum concentration (tmax) was 4.0 minutes. Median fluticasone propionate tmax was from 1.5 to 2.0 hours. Terminal elimination half-life was 11 hours for salmeterol and 9-10 hours for fluticasone propionate. CONCLUSIONS: Salmeterol/fluticasone Easyhaler was shown to be bioequivalent with the reference product.

Salmeterol undergoes enantioselective bronchopulmonary distribution with receptor localisation a likely determinant of duration of action.

BACKGROUND: Salmeterol (a long acting beta2-agonist) is a chiral molecule. (RR)-salmeterol is responsible for pharmacological effect, but basic knowledge of enantioselective pulmonary pharmacodynamics and pharmacokinetics of salmeterol remains unknown. There are safety concerns with (S)-enantiomers of beta2-agonists, with suggestions that these enantiomers may increase bronchial hyperresponsivneness in asthma patients. METHODOLOGY: Horses (n = 12) received racemic (rac-) salmeterol 250 µg via inhalation. Enantioselective UPLC-MS/MS was used to determine (R)- and (S)-salmeterol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15 min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25 min respectively), and in plasma samples. RESULTS: Physiologically relevant tissue concentrations were found for both enantiomers, with median levels greater in central than peripheral lung (equivalent to 32 and 5 mM (R)-salmeterol for central and peripheral lung respectively). Levels in PELF decreased around 50% over 15 min and enantioselective distribution was observed in the central lung with levels of (R)-salmeterol around 30% higher than (S)-salmeterol. CONCLUSION: Salmeterol distribution is enantioselective in the central lung. This suggests duration of action is more likely associated with specific B2ADR localisation effects rather than non-specific physiochemical factors which would not be enantioselective.

Uncovering the regional localization of inhaled salmeterol retention in the lung.

Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d3-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

Application of a One-Dimensional Computational Model for the Prediction of Deposition from a Dry Powder Inhaler.

BACKGROUND: Accurate prediction of the regional deposition of inhaled dry powders as a function of powder properties and breathing pattern is a long-term research goal for pulmonary drug delivery. In the present work, deposition along the respiratory tract of dry powders of Fluticasone propionate and Salmeterol is predicted. METHODS: A one-dimensional particle transport and deposition model is used, whose novelty is in the treatment of the alveolar space of each airway generation as an efficient mixing chamber. This assumption has been supported by simulations and measurements during the last 20 years. The model is applied to two popular pulmonary tree geometries, to investigate the effect of particle size on localized deposition and to estimate the uncertainty due to variations in airway size. RESULTS AND CONCLUSIONS: Application of the model for the specific particle size distribution measured by a cascade impactor in the marketed product ELPENhaler, predicts the whole lung deposition (WLD), as well as the split between pulmonary (PU) and tracheobronchial (TB) deposition. Introduction in the model of modified particle size distributions with increased fractions of fine particles, indicates that the fine-particle dose is a satisfactory predictor of WLD but not of the PU/TB ratio.

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers.

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.

Detection and pharmacokinetics of salmeterol in thoroughbred horses following inhaled administration.

Salmeterol is a man-made beta-2-adrenergic receptor agonist used to relieve bronchospasm associated with inflammatory airway disease in horses. Whilst judicious use is appropriate in horses in training, they cannot race with clinically effective concentrations of medications under the British Horseracing Authority's Rules of Racing. Salmeterol must therefore be withdrawn prior to race day and pharmacokinetic (PK) studies used to establish formal detection time advice. Salmeterol xinafoate (Serevent Evohaler® ) was administered (0.1 mg twice daily for 4.5 days) via inhalation to six horses. Urine and blood samples were taken up to 103 h postadministration. Hydrolysed samples were extracted using solid phase extraction. A sensitive Ultra high performance tandem mass spectrometry (UPLC-MS/MS) method was developed, with a Lower limit of quantification (LLOQ) for salmeterol of 10 pg/mL in both matrices. The majority of salmeterol plasma concentrations, postlast administration, were below the method LLOQ and so unusable for PK analysis. Urine PK analysis suggested a half-life consistent with duration of pharmacological effect. Average estimated urine concentration at steady-state was obtained via PK modelling and used to estimate a urine concentration of 59 ± 34 pg/mL as a marker of effective lung concentration. From this, potential detection times were calculated using a range of safety factors.

Cell membranes and how long drugs may exert beneficial pharmacological activity in vivo.

The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future.

Bioassay of salmeterol in children using methacholine challenge with impulse oscillometry.

BACKGROUND: Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). METHODS: This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4-11 years. None were taking a long-acting ß-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 µg salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 µg salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40 R5 ) was calculated. RESULTS: The reduction in R5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 µg, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95%CI) PC40 R5 (mg/ml) was 2.4 (1.3-4.4) during screening, 22.9 (8.5-61.6) after 50 µg SM and 47.0 (25.2-87.8) after 100 µg SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. CONCLUSIONS: MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. Pediatr Pulmonol. 2016;51:570-575. © 2015 Wiley Periodicals, Inc.

Evaluation of a Scenario in Which Estimates of Bioequivalence Are Biased and a Proposed Solution: tlast (Common).

In bioequivalence (BE) testing, it is the convention to identify tlast separately for each concentration-vs-time profile. Within-subject differences in tlast between treatments can arise when assay sensitivity is reached during washout, causing profiles to fall below the limit of quantitation (LOQ) at different sampling times. The resulting tlast difference may be systematic, due to true differences in exposure, and/or random, due to measurement noise. The conventional profile-specific tlast approach assumes that concentrations in the terminal phase are sufficiently low that use of different tlast values between treatments within a subject causes negligible bias in the AUC0-t geometric mean ratio (GMR). Here we investigate the validity of this assumption. Using concentration-vs-time data following oral inhalation of 50 µg salmeterol as an example data set, we conducted simulations to evaluate whether use of different test/reference AUC timeframes arising from a systematic difference in exposure causes sufficient AUC0-t GMR bias to influence the determination of BE. To ensure that results would be relevant to BE testing, we considered only test/reference relative systemic exposures within the BE window (80.00%-125.00%). We show that use of conventional profile-specific tlast exaggerates true differences in systemic exposure; the resulting AUC0-t ratios are biased from true relative exposure by an amount large enough to impact the conclusion of BE. Thus, drugs whose concentrations fall below LOQ during washout may fail BE inappropriately using conventional methods. AUC0-t calculated over a common timeframe within each subject (tlast [common]) minimizes this bias and harmonizes the statistical analysis of BE.

Budesonide/salmeterol in fixed-dose combination for the treatment of asthma.

Fixed dose combinations (FDC) of inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) are well established in asthma treatment. The budesonide/salmeterol (B/S) FDC is now about to reach the market. It is provided as powder in hard capsules of two strengths: 120/20µg and 240/20µg when expressed as delivered doses, equivalent to 150/25µg and 300/25µg when expressed as nominal doses. Its development involved 9 pharmacokinetic (320 subjects), 3 phase II (123 subjects) and 4 phase III (1206 patients with different asthma severity) studies. Delivery is effectuated via low resistance inhaler device, Axahaler®, generating also fine particles targeting the small airways. B/S safety, assessed in 1401 subjects, did not outline novel concerns specific for this FDC. In conclusion, the B/S dry powder FDC can be used for asthma treatment in adults not adequately controlled on ICS alone, or to maintain control of ICS/LABA treated patients, in whom switching to alternative FDC is indicated.

Enhanced oral bioavailability of salmeterol by loaded PLGA microspheres: preparation, in vitro, and in vivo evaluation.

The objective of the current study was to prepare microspheres of salmeterol (SM) using poly (lactide-co-glycolide) (PLGA) and assess its viability to enhance the oral bioavailability. Microspheres of SM were prepared by oil-in-water emulsion-solvent evaporation method. The formulations were characterized in encapsulation efficiency, particle size, zeta potential, and in vitro release. The prepared microspheres were found to be spherical in shape with smooth surface. The size of microspheres ranged from 14.7 to 16.5 µm. The polydispersity index (PDI) was 0.12 ± 0.05 and the zeta potential was -33.2 ± 1.4 mV. In vitro release profile, SM was graduated released from the microspheres as time lapsed, suggesting that SM was well entrapped in SM-loaded PLGA microspheres. The model that fitted best for SM released from the microspheres was Higuchi equation. In vivo study, SM-loaded PLGA microspheres are thought to have the potential to maintain SM concentration within target ranges for a long time, decreasing side effects caused by concentration fluctuation, ensuring the efficiency of treatment and improving patient compliance by reducing dosing frequency.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.

Beta-2 Adrenergic Agonists Are Substrates and Inhibitors of Human Organic Cation Transporter 1.

Beta-2-adrenergic agonists are first line therapeutics in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Upon inhalation, bronchodilation is achieved after binding to ß2-receptors, which are primarily localized on airway smooth muscle cells. Given that ß2-adrenergic agonists chemically are bases, they carry net positive charge at physiologic pH value in the lungs (i.e., pH 7.4). Here, we studied whether ß2-agonists interact with organic cation transporters (OCT) and whether this interaction exerted an influence on their passage across the respiratory epithelium to their target receptors. [14C]-TEA uptake into proximal (i.e., Calu-3) and distal (i.e., A549 and NCI-H441) lung epithelial cells was significantly reduced in the presence of salbutamol sulfate, formoterol fumarate, and salmeterol xinafoate in vitro. Expression of all five members of the OCT/N family has been confirmed in human pulmonary epithelial cells in situ and in vitro, which makes the identification of the transporter(s) responsible for the ß2-agonist interaction challenging. Thus, additional experiments were carried out in HEK-293 cells transfected with hOCT1-3. The most pronounced inhibition of organic cation uptake by ß2-agonists was observed in hOCT1 overexpressing HEK-293 cells. hOCT3 transfected HEK-293 cells were affected to a lesser extent, and in hOCT2 transfectants only marginal inhibition of organic cation uptake by ß2-agonists was observed. Bidirectional transport studies across confluent NCI-H441 cell monolayers revealed a net absorptive transport of [3H]-salbutamol, which was sensitive to inhibition by the OCT1 modulator, verapamil. Accordingly, salbutamol uptake into hOCT1 overexpressing HEK-293 cells was time- and concentration-dependent and could be completely blocked by decynium-22. Taken together, our data suggest that ß2-agonists are specific substrates and inhibitors of OCT1 in human respiratory epithelial cells and that this transporter might play a role in the pulmonary disposition of drugs of this class.