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Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract., Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid., Results: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline., Conclusions: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy., (© 2024 Genentech and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are prevalent in patients with asthma. These disorders may increase asthma severity and decrease asthma control. No studies have evaluated the impact of achieving antidepressant target dose optimization compared with not achieving antidepressant target doses on asthma control in uninsured and underinsured patients., Objective: To evaluate the impact of achieving antidepressant target dose optimization in uninsured and underinsured adult asthma patients with GAD and/or MDD on the risk of severe asthma exacerbations and number of asthma-related outcomes., Methods: We conducted a retrospective cohort study of uninsured and underinsured adult asthma patients with GAD and/or MDD who have been initiated on a single antidepressant and maintained on a stable dose for 8 weeks (index date). Eligible patients were followed for 12-24 months after the index date and separated into those who achieved a target dose (target group) and those who did not (control group). Poisson regression was used to compare the risk of severe exacerbations, and analysis of covariance was used to compare the number of severe exacerbations and other asthma-related outcomes between the target and control groups during the 1- and 2-year post-index periods., Results: A total of 61 patients (24 in the target group and 37 in the control group) met inclusion criteria. The target group had a reduced risk of severe asthma exacerbations compared with the control group during the 1-year post-index (adjusted risk reduction [RR] 0.46, 95% confidence interval [CI] 0.26-0.82) and 2-year post-index (adjusted RR 0.5, 95% CI 0.3-0.82) periods. The target group also experienced a lower number of severe asthma exacerbations and other asthma-related outcomes during the 1- and 2-year post-index periods compared with the control group after adjusting for confounders., Conclusions: Among uninsured and underinsured asthma patients with GAD and/or MDD who were initiated on a single antidepressant, those who were titrated to achieve target doses had a reduced risk of severe asthma exacerbations and a lower number of asthma-related outcomes than those who were not optimized to achieve target doses., (© 2020 Pharmacotherapy Publications, Inc.)

Aim: The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma., Methods: This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours., Results: In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80-1.25, both for beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively., Conclusions: In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting β2 -adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults., (© 2015 The British Pharmacological Society.)

Aim: The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children., Methods: Children aged 5-11 years old inhaled BDP 200 μg and formoterol 24 μg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, Cmax , tmax , t1/2 ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored., Results: Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml(-1)  h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml(-1)  h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related., Conclusion: BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5-11-year-old asthmatic children., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Objectives/hypothesis: The aim of this study was to investigate possible interactions between grapefruit juice and montelukast for up to 4 hours., Study Design: A prospective, crossover study with 23 healthy volunteers was performed in two sessions., Methods: In the first session, volunteers were treated with oral montelukast 10 mg once daily with 250 ml water. After a 10-day washout period, the same volunteers were treated with 10 mg montelukast with 250 ml grapefruit juice. Blood samples were collected 2, 3, and 4 hours after drug administration and kept at -80°C after both applications. Plasma samples were analyzed for montelukast concentration., Results: The mean plasma concentration of montelukast across all time intervals was significantly greater (P = 0.0001) for those given grapefruit juice (517, 484, and 440) versus those treated with water (366, 356, and 292). Moreover, with respect to the time the sample was collected, there was no significant difference (P = 0.13) in the mean total plasma concentration up to 4 hours after montelukast ingestion for either group. There was a significant difference between the groups according to the area under curve with regard to marginal and cumulative values for all different time intervals (P < 0.05)., Conclusions: Plasma concentration of montelukast was higher when administered with grapefruit juice, as compared to with water. This may have been due to the effect of grapefruit on liver metabolism of montelukast and the cytochrome P450 system., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Background: To which extent volume spacers may influence systemic activity of inhaled beclomethasone dipropionate (BDP) has not been evaluated., Aim: To assess whether the AeroChamber Plus™ spacer is equivalent to the Volumatic™ spacer for administration of inhaled hydroflouroalkane 134a propelled BDP in terms of lower leg growth rate (LLGR)., Patients and Methods: Prepubertal children with mild asthma (n = 26, aged 6-14 years) were included in a 3-time periods of 2 weeks duration randomized double-blind cross-over study with a single-blind placebo run-in and two washout periods. LLGR was measured with the knemometer. Interventions were inhaled BDP hydroflouroalkane 134a pressurized metered dose inhaler 100 μg and 200 μg b.i.d. with the AeroChamber Plus and 200 μg b.i.d. with the Volumatic spacer., Results: Beclomethasone dipropionate 200 μg b.i.d. from the AeroChamber Plus was non-inferior to BDP 200 b.i.d. from the Volumatic spacer as the lower margin of confidence interval of the difference between treatments (-0.18 to 0.13 mm/week) was greater than the prespecified lower limit for non-inferiority (-0.20 mm/week). UFC/creatinine data showed no statistically significant variations., Conclusion: The systemic activity of BDP, via the Volumatic™, and AeroChamber Plus™ spacers is similar. The AeroChamber Plus spacer may be used in children without risk of increasing systemic activity of BDP., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Aim: According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast., Methods: In a randomized crossover study, 11 healthy subjects ingested gemfibrozil 600 mg, itraconazole 100 mg (first dose 200 mg) or both, or placebo twice daily for 5 days, and on day 3, 10 mg montelukast. Plasma concentrations of montelukast, gemfibrozil, itraconazole and their metabolites were measured up to 72 h., Results: The CYP2C8 inhibitor gemfibrozil increased the AUC(0,∞) of montelukast 4.3-fold and its t(1/2) 2.1-fold (P < 0.001). Gemfibrozil impaired the formation of the montelukast primary metabolite M6, reduced the AUC and C(max) of the secondary (major) metabolite M4 by more than 90% (P < 0.05) and increased those of M5a and M5b (P < 0.05). The CYP3A4 inhibitor itraconazole had no significant effect on the pharmacokinetic variables of montelukast or its M6 and M4 metabolites, but markedly reduced the AUC and C(max) of M5a and M5b (P < 0.05). The effects of the gemfibrozil-itraconazole combination on the pharmacokinetics of montelukast did not differ from those of gemfibrozil alone., Conclusions: CYP2C8 is the dominant enzyme in the biotransformation of montelukast in humans, accounting for about 80% of its metabolism. CYP3A4 only mediates the formation of the minor metabolite M5a/b, and is not important in the elimination of montelukast. Montelukast may serve as a safe and useful CYP2C8 probe drug., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Background: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics., Objective: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC)., Methods: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods., Results: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration., Conclusions: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma., (© 2011 John Wiley & Sons A/S.)

What Is Already Known About This Subject: Omalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized., What This Study Adds: (i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy., Aim: To determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy., Methods: Omalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change., Results: The prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3-5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building., Conclusions: A pharmacokinetic-pharmacodynamic model incorporating omalizumab-IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Aim: To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK)., Methods: An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 microm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 microg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K(+)) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min., Results: The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K(+) revealed a significant dose-response with a non-significant T : R ratio., Conclusions: The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 microg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

Aim: To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids., Methods: A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n= 25) or without reversible bronchoconstriction (Rev-; n= 16). A dose of 0.10 U kg(-1) inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order)., Results: Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P= 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C(max)) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P= 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C(max) was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P= 0.044) and the whole group (P= 0.032)., Conclusions: In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.

Background: Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4Ralpha and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum-sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action., Methods: Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment., Results: Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC(100) relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05-0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC(100) relative to control (P < 0.05) at nominal b.i.d. doses of 3-100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control., Conclusion: Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.

Aims: Omalizumab, a subcutaneously administered anti-IgE antibody, is effective for moderate-to-severe persistent allergic asthma. The aims were to (i) describe the population pharmacodynamics of free IgE with a mechanism-based, nonlinear, omalizumab-IgE binding model; (ii) deduce a target-free IgE suppression level by correlation with clinical outcomes; and (iii) check the adequacy of current approved dosing tables and explore potential doses and regimens beyond., Methods: Concentration data (omalizumab, free and total IgE) were obtained from 1781 patients aged 12-79 years, in four sparsely sampled randomized, placebo-controlled studies and 152 subjects in a richly sampled single-dose study. NONMEM predictive performance across the range of bodyweights (39-150 kg) and baseline IgE (19-1055 IU ml(-1)) was checked by simulation. Predicted free IgE levels were correlated with time-averaged patient diary clinical outcomes., Results: The model accurately predicted observed omalizumab, free and total IgE concentrations. Free IgE concentrations correlated well with clinical signs and symptoms, allowing a target concentration of 14 ng ml(-1), at the midpoint of 4-week clinical observation periods, to be set for determining the dose and regimen for omalizumab., Conclusions: The omalizumab-IgE binding model is predictive for free IgE and demonstrates a nonlinear time-dependent relationship between free IgE suppression and clinical outcomes in asthma. Although currently approved dosing tables are close to optimal, it should be possible to treat patients with higher levels of baseline IgE if higher doses can be administered.

What Is Already Known About This Subject: Conventional spacers help overcome problems with co-ordination and may improve lung deposition and decrease oropharyngeal impaction. Antistatic spacers eliminate electrostatic charge and may hence improve respirable dose delivery. The systemic bioavailability of inhaled fluticasone propionate is primarily dependent on delivery by the pulmonary route and hence the performance of antistatic spacers can be evaluated using adrenal suppression as a sensitive surrogate for relative bioavailability to the lung after an inhalation., What This Study Adds: This study compares the relative bioavailability to the lung of inhaled fluticasone delivered via conventional pressurized metered dose inhalers (pMDI) and three antistatic spacers (plastic Zerostat-V, plastic Aerochamber Max, and metal Nebuchamber) in patients with asthma. All three antistatic spacers when compared with pMDI significantly increased the relative bioavailability to the lungs of inhaled fluticasone in terms of relative adrenal suppression, and there were no significant differences between the plastic and metal antistatic spacers., Aims: The systemic bioavailability of inhaled fluticasone propionate (FP) depends primarily on lung absorption and can be quantified by measuring suppression of overnight and early morning urinary cortisol/creatinine (OUCC and EMUCC, respectively). The aim of the study was to determine the relative bioavailability of hydrofluoroalkane (HFA) FP to the lungs via anti-static plastic (Zerostat-V and Aerochamber Max), metal (Nebuchamber) anti-static spacers and metered dose inhaler [Flixotide Evohaler (EH) (pMDI)]., Methods: A randomized, double-blind, double-dummy, four-way crossover design was used. Eighteen mild to moderate asthmatics received single doses of placebo/HFA-FP 2 mg via the 280-ml Zerostat-V (ZS); 250-ml Nebuchamber (NC); 197-ml Aerochamber Max (AC); and pMDI (EH). Measurements of OUCC and EMUCC were made at baseline and 10 h after each dose., Results: Significant suppression of OUCC and EMUCC occurred from baseline with all three spacers, but not Evohaler (geometric mean fold suppression, 95% confidence interval): ZS, 2.74 (1.75, 4.30), P < 0.001; NC, 3.31 (1.81, 6.06), P < 0.001; AC, 4.98 (3.39, 7.31), P < 0.001; and for EH this was 1.42 (0.92, 2.21), P= 0.169 (equating to a 64, 70, 80 and 30% fall in OUCC via the ZS, NC, AC and EH devices, respectively). There were significant differences between all three spacers vs. EH. When compared with the Evohaler, the Zerostat V resulted in 48% greater suppression (P= 0.009); the Nebuchamber 57% greater suppression (P= 0.001); and the Aerochamber Max 71% greater suppression of OUCC (P < 0.001)., Conclusion: All three antistatic spacers significantly increased the relative systemic bioavailability of HFA-FP compared with the standard pMDI. --EudraCT Database trial registration number: 2005-005557-22.

Aims: For optimal efficacy, antiasthma drugs should be delivered to the desired region in the airways. To date, the optimal particle size for steroids in adults is not known. The aim of the study was to evaluate the pulmonary bioavailability for inhaled beclomethasone dipropionate (BDP) aerosols of different particle sizes., Methods: In a randomized single-blind crossover trial, 10 mild asthmatic patients inhaled monodisperse BDP aerosols with mass median aerodynamic diameters (MMADs) of 1.5, 2.5 and 4.5 microm. Gastrointestinal absorption was blocked by activated charcoal. Plasma concentrations of 17-beclomethasone monopropionate (17-BMP) were measured by liquid chromatography plus mass spectrometry., Results: Aerosols with MMADs of 1.5 microm, 2.5 microm, and 4.5 microm gave mean maximum concentrations (C(max)) of 17-BMP of 475 pg ml(-1), 1300 pg ml(-1), and 1161 pg ml(-1), respectively. The area under the curve (AUC) values of 17-BMP for MMADs of 1.5 microm, 2.5 microm, and 4.5 microm were 825 pg ml(-1) h, 2629 pg ml(-1) h, and 2276 pg ml(-1) h, respectively. The mean terminal half-time of 17-BMP for all three aerosol sizes was around 1.5 h., Conclusions: Monodisperse BDP aerosols with a MMAD of 1.5 microm gave two-three fold lower values for C(max) and AUC than those with MMADs of 2.5 and 4.5 microm.

Aims: Budesonide, a glucocorticosteroid, is used as a first-line treatment for asthma. The aim of the study was to develop a PK/PD model for the effect of budesonide on ACTH and cortisol., Methods: The modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 microg budesonide (Pulmicort Turbohaler), with a wash-out period of 7 days between treatments. Baseline concentrations of cortisol and ACTH were measured after placebo treatment and concentrations of cortisol, ACTH and budesonide were assessed after budesonide treatment. A one-compartment disposition model was used for budesonide disposition. Based on indirect response models, two types of models, distinguishing between production driven by a sum of cosine functions and production driven by surges, were used in parallel to describe the data., Results: The surge-based approach was the most appropriate, based on goodness-of-fit, objective function values and number of parameters. The surge-based model that integrated both ACTH and cortisol data was chosen as the final model. The estimated half-lives of endogenous ACTH and cortisol were 9 and 113 min, respectively. The budesonide and ACTH concentrations producing 50% of the maximal response (IC(50) and A(50)) were 0.325 microg l(-1) and 4.96 pmol l(-1)., Conclusions: The present PK/PD model of the effect of budesonide on ACTH and cortisol can serve as a tool for further understanding of the hypothalamic-pituitary-adrenal (HPA) axis and be useful in the development of drugs interacting with the axis.

Aims: To compare the pharmacokinetic profiles of beclometasone, budesonide, fluticasone and mometasone following inhalation in patients with asthma, and explore the relationship between lung function and plasma drug concentrations., Methods: Thirty subjects with asthma and a forced expiratory volume in 1 s (FEV(1)) ranging from 36 to 138% predicted, inhaled 800 microg beclometasone, budesonide and mometasone and 1000 microg fluticasone in random order. Plasma drug concentrations were measured over 8 h and the relationship between the area under the plasma concentration-time curve (AUC(0-8)) and lung function was modelled using linear regression. Estimated AUC(0-8) values at 50 and 100% predicted FEV(1) were compared for each drug., Results: Pharmacokinetic profiles differed markedly between the drugs. Correlation coefficients for the relation between FEV(1)% predicted and AUC(0-8) values for beclometasone, budesonide, fluticasone and mometasone were 0.37 (P = 0.05), 0.33 (P = 0.08), 0.25 (P = 0.2) and 0.52 (P = 0.004), respectively, and estimated AUC(0-8) values were 1.3 [95% confidence interval (CI) 1.0, 1.8], 1.3 (95% CI 1.0, 1.8), 1.4 (95% CI 0.9, 2.2) and 2.2 (95% CI 1.3, 3.5) times higher for the four drugs, respectively, at 100 compared with 50% predicted FEV(1.), Conclusion: The higher plasma concentrations of inhaled corticosteroids in patients with a higher FEV(1)% predicted suggests that, for any given dose, these patients will be at greater risk of developing adverse systemic effects with long-term use.

Aims: With the recent introduction of hydrofluoroalkane (HFA) inhalers it is important to know the relative systemic safety profiles of inhaled corticosteroids. We therefore decided to compare systemic bioavailability of HFA-beclomethasone dipropionate (BDP) vs HFA-fluticasone propionate (FP)., Methods: Sixteen healthy volunteers were randomised in placebo-controlled single blind cross-over fashion to receive 3 weeks with HFA-FP or HFA-BDP, given as 1 week cumulative doubling doses (nominal ex-valve) of 500, 1000 and 2000 microg day(-1), with a 1 week placebo run-in and wash-out. Overnight (22.00 h to 08.00 h) and early morning (08.00 h) urinary cortisol/creatinine excretion and 08.00 h serum cortisol were measured after each placebo and dosing period. All data were log-transformed to normalize their distribution., Results: Urine and serum cortisol were suppressed by 2000 microg FP and BDP vs placebo and by 1000 microg BDP vs placebo for urinary cortisol/creatinine (P < 0.05). Overnight urinary cortisol/creatinine ratio (the primary endpoint) was suppressed more by 1000 microg BDP vs 1000 microg FP (P < 0.05), amounting to a geometric mean fold difference (95% CI) of 1.64 (1.04-2.56). There were also more individual low values less than 3 nmol mmol(-1) with BDP than FP at 1000 microg: n = 8/16 vs n = 2/16 (P < 0.05)., Conclusions: There was dose-related suppression of corrected urinary cortisol/creatinine with the HFA formulations of BDP and FP. Suppression of overnight urinary cortisol/creatinine ratio was significantly greater with HFA-BDP than HFA-FP at 1000 microg. This suggests that the greater glucocorticoid potency of HFA-FP may be offset by the greater lung bioavailability of HFA-BDP.

Aims: To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration., Methods: Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 microg), oral (4000 microg, aqueous suspension), intranasal (1344 microg, aqueous nasal spray) and inhaled (1000 microg ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was assessed by repeating the inhaled, intranasal and oral dosing arms together with activated charcoal, to block oral absorption. Blood samples were collected for 24 h postdose for the measurement of BDP, beclomethasone-17-monopropionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chromatography tandem mass spectrometry., Results: Intravenous administration of BDP (mean CL 150 l h-1, Vss 20 l, t(1/2) 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h-1, Vss 424 l) complete conversion of BDP to B-17-MP was assumed. The resultant plasma concentrations of BOH were low and transient. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP was 2% (1-4%) and not reduced by coadministration of charcoal. The mean percentage F of the active metabolite B-17-MP was 41% (31-54%), 44% (34-58%) and 62% (47-82%) for oral, intranasal and inhaled dosing without charcoal, respectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were < 1% and 36% (27-47%), respectively., Conclusions: Unchanged BDP has negligible oral and intranasal bioavailability with limited absorption following inhaled dosing due to extensive (95%) presystemic conversion of BDP to B-17-MP in the lung. The oral and intranasal bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insignificant. The total inhaled bioavailability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this was due to pulmonary absorption. Estimates of oral bioavailability and pulmonary deposition based on total BOH were approximately half those found for B-17-MP.

Aims: Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat-dose inhalation., Methods: This pharmacokinetic substudy was part of a previously published open-label, randomised, placebo-controlled, 7-period crossover study to evaluate the short-term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 microg twice daily) and FP (375, 750, 1000 microg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 microg twice daily and FP 1000 microg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non-compartmental analysis and a mixed effects model were used to characterize the disposition profiles., Results: Both drugs had a rapid absorption half-life (BUD 10 min vs FP 11.3 min), but quite different elimination half-lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R-and 22S-epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP's higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung., Conclusions: This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t(1/2),z for BUD, resulting in higher and more sustained plasma drug levels in the 4-12 h postdose period than would be predicted from single-dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher-than-expected plasma drug concentrations in the morning compared with the evening.

Studies involving the direct measurement of clinical response to inhaled asthma drugs, especially inhaled corticosteroids, may be very difficult to conduct. However, the deposition of drug in the lungs may be considered as a measure of local bioavailability, and may be quantified by radionuclide imaging techniques, or for some drugs by pharmacokinetic methods. This paper reviews evidence for considering lung deposition data as a surrogate for the clinical response to inhaled asthma drugs, based mainly upon a series of case histories. The appropriate use of lung deposition data in regulatory packages, especially to document the equivalence or comparability of two products, offers the possibility of significant time saving in the drug development process, and hence a faster drug development programme for inhaled asthma products.

Aims: To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method., Results: No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) microg, 10.4 (10.9) microg and 83.7 (71.1) microg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) microg, 61.2 (28.3) microg and 305.6 (82.3) microg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) microg, 49.3 (18.1) microg and 184.9 (98.4) microg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h., Conclusions: The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.

Studies have shown that the receptors for beta-agonists, inflammatory markers, and mast cells are distributed throughout the airways. Thus topical delivery of drug for the management of asthma requires an even spread throughout the lungs. Particles of 2-5 microm in diameter have the greatest potential to be deposited throughout the lungs during inhalation, by impaction and sedimentation. Inhaled products, therefore, are formulated such that almost half of the dose emitted during inhalation contains particles less than 5 microm in diameter. This is known as the fine-particle dose. Studies in adults (volunteers and asthmatic patients), using radiolabeling techniques, have shown that although the amount of drug deposited in the airways (total lung dose) from different inhaled products varies, the percentages of this amount distributed throughout the central, intermediate, and peripheral zones are fairly consistent. All that varies, therefore, is the density of the spread. Studies in children indicate that lung deposition is lower than in adults. Nevertheless, all factors which affect lung deposition in adults do so also in children. The lower lung deposition in children indicates the use of adult doses, and the importance of inhaler device and of inhalation technique. The even distribution of inhaled drug throughout the required therapeutic areas highlights the importance of the total lung dose.

Aims: To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration., Methods: Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed., Results: Statistically significant (P < 0.05) increases were noted in AUC(o,t) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71-1.84)., Conclusions: Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night-time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.

Aims: The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation., Methods: Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 micrograms) of FP via Diskhaler and repeated inhalations (1000 micrograms twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 micrograms FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values., Results: The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectivley., Conclusions: To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.

1. Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000 micrograms dose range. 2. The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (Vss 3181), rapidly cleared (CL 1.1 l min-1) with a terminal elimination half-life of 7.8 h and a mean residence time of 4.9 h. 3. In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.