A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.     

Evaluation of the administration time effect on the cumulative cortisol suppression and cumulative lymphocytes suppression for once-daily inhaled corticosteroids: a population modeling/simulation approach

Inhaled glucocorticoids continue to be first-line therapy in asthma. To improve improving patient compliance, newer inhaled glucocorticoids have been developed for once-a-day treatment. This study was interested in identifying the optimal time of dosing using 2 surrogate markers of glucocorticoid action. A previously published study on the pharmacokinetics and pharmacodynamics (cortisol and blood lymphocyte suppression) of the inhaled glucocorticoids budesonide and fluticasone propionate was reanalyzed using a population pharmacokinetic approach. A stochastic numerical simulation using NONMEM assessed the effects of time of dosing on cortisol (side effect parameter) and blood lymphocytes (side effect and effect parameter). The effects on cortisol were more pronounced when the glucocorticoids were given in the morning, whereas the effects on lymphocytes (an effect controlled by endogenous and exogenous glucocorticoids) were maximized when dosing occurred in the late afternoon or evening. Twice-daily dosing of the same dose resulted in smaller differences between maximum and minimal effects. These were of no clinical relevance. Simulations for once-daily dosing support clinical studies that reported a higher antiasthmatic effect and lower cortisol suppression when once-daily dosing occurs in the evening.     

An assessment of asthma exacerbations in pediatric patients using a long-acting B2-agonist plus inhaled corticosteroid versus an inhaled corticosteroid alone

BackgroundAn asthma exacerbation is an anticipated sudden worsening of the disease severity, which usually does not respond to conservative therapy. The management of asthma depends on the severity of the disease symptoms, which includes an inhaled corticosteroid (ICS) and a bronchodilator. This study aimed to assess the efficacy of combining a long-acting B2-agonist (LABA) with ICS, compared to ICS alone, to reduce the incidence of asthma exacerbations in pediatric patients, diagnosed with severe persistent asthma.MethodsA retrospective analysis of the medical records was conducted for 586 children, admitted to the Emergency Department (ED) at King Abdullah Specialized Children Hospital in Riyadh, Saudi Arabia, for the management of severe persistent asthma symptoms, from January 2016 to September 2019.ResultsThe majority (n = 480, 81.9%) of the patients received fluticasone (Flovent)® as the standard of care ICS treatment for controlling asthma, and a small proportion (n = 106, 18.1%) were treated with a combination of LABA and ICS. A significant increase in the frequency of recurrent asthma exacerbation episodes occurred in the group receiving ICS alone (98.5%), compared to 67.0% in the combination group (p < 0.0001). Moderate to severe exacerbations were significantly higher in the ICS group compared to the combination group (95.6% versus 84.5%, respectively, p = 0.0005).ConclusionsThe current results confirm the substantial efficacy of the LABA/ICS combination therapy in reducing the incidence and severity of asthma exacerbations in pediatric patients, compared to ICS alone.     

The newly developed inhaled corticosteroid ciclesonide for the treatment of asthma

Ciclesonide is the most recently developed inhaled corticosteroid for the treatment of asthma to enter global markets. It has been formulated as an aerosol solution in a metered dose inhaler with hydrofluoralkane. The mass median aerodynamic diameter of aerosolised ciclesonide is 1 – 2 µm, providing excellent lung deposition characteristics. Ciclesonide can undergo reversible esterification in the lungs, possibly allowing once-daily dosing, and is highly protein bound, possibly leading to reduced systemic side effects. Clinical trials suggest that ciclesonide effectively controls asthma and has a favourable safety profile.     

The newly developed inhaled corticosteroid ciclesonide for the treatment of asthma

Ciclesonide is the most recently developed inhaled corticosteroid for the treatment of asthma to enter global markets. It has been formulated as an aerosol solution in a metered dose inhaler with hydrofluoralkane. The mass median aerodynamic diameter of aerosolised ciclesonide is 1 - 2 microm, providing excellent lung deposition characteristics. Ciclesonide can undergo reversible esterification in the lungs, possibly allowing once-daily dosing, and is highly protein bound, possibly leading to reduced systemic side effects. Clinical trials suggest that ciclesonide effectively controls asthma and has a favourable safety profile.     

Fluticasone propionate: a potent inhaled corticosteroid for the treatment of asthma

Fluticasone propionate (FP) is a potent inhaled corticosteroid (ICS) for the treatment of asthma. It is currently marketed in both the United States (as Flovent^®) and Europe (as Flixotide^®). Fluticasone is available in both aerosolised metered dose inhaler (MDI) and dry powder devices, with dosages ranging from 44 - 500 μg/puff. FP has been extensively studied in both children and adults; efficacy has been documented across the entire spectrum of asthma severity, including corticosteroid-dependent disease. Clinical data with FP strongly corroborates the in vitro pharmacokinetic and pharmacodynamic studies that FP is at least twice as potent as beclomethasone dipropionate (BDP), budesonide (BUD) or triamcinolone acetonide (TAA). Both objective (lung function) and subjective (symptoms, β-agonist use and quality of life) outcomes are improved with FP treatment. Extensive post-marketing surveillance with FP suggests that it is more cost-effective than BUD and flunisolide (FLU) when analysed by an overall healthcare cost perspective. Most of the benefits arise from decreased hospitalisations, emergency room visits and physician-office visits. Extensive safety data with FP documents no clinically meaningful effects on bone mass, nor impairment of growth velocity in children. Considering the efficacy and safety data along with the ability to optimise patient’s asthma therapy using the delivery devices and strengths available, FP has become a leader in the ICS marketplace to date.     

Fluticasone propionate: a potent inhaled corticosteroid for the treatment of asthma

Fluticasone propionate (FP) is a potent inhaled corticosteroid (ICS) for the treatment of asthma. It is currently marketed in both the United States (as Flovent) and Europe (as Flixotide). Fluticasone is available in both aerosolised metered dose inhaler (MDI) and dry powder devices, with dosages ranging from 44-500 micrograms/puff. FP has been extensively studied in both children and adults; efficacy has been documented across the entire spectrum of asthma severity, including corticosteroid-dependent disease. Clinical data with FP strongly corroborates the in vitro pharmacokinetic and pharmacodynamic studies that FP is at least twice as potent as beclomethasone dipropionate (BDP), budesonide (BUD) or triamcinolone acetonide (TAA). Both objective (lung function) and subjective (symptoms, beta-agonist use and quality of life) outcomes are improved with FP treatment. Extensive post-marketing surveillance with FP suggests that it is more cost-effective than BUD and flunisolide (FLU) when analysed by an overall healthcare cost perspective. Most of the benefits arise from decreased hospitalizations, emergency room visits and physician-office visits. Extensive safety data with FP documents no clinically meaningful effects on bone mass, nor impairment of growth velocity in children. Considering the efficacy and safety data along with the ability to optimise patient's asthma therapy using the delivery devices and strengths available, FP has become a leader in the ICS marketplace to date.     

孟鲁司特联合吸入糖皮质激素治疗小儿轻度持续哮喘

目的:探讨孟鲁司特联合吸入糖皮质激素治疗小儿轻度持续哮喘的临床疗效.方法:观察孟鲁司特联合吸入糖皮质激素30例(治疗组)与单纯吸入糖皮质激素22例(对照组)的总体疗效.结果:孟鲁司特联合糖皮质激素吸入组总有效率96.1%,单纯糖皮质激素吸入组总有效率68.1%,两组之间差异有统计学意义(χ2=5.874,P＜0.05).结论:孟鲁司特联合吸入糖皮质激素治疗小儿轻度持续哮喘效果明显.     

Cost effectiveness of inhaled corticosteroid plus bronchodilator therapy versus bronchodilator monotherapy in children with asthma

In an incremental cost-effectiveness analysis, combined inhaled beta 2-receptor agonist plus inhaled corticosteroid therapy (BA + CS) was compared with inhaled beta 2-agonist plus placebo (BA + PL) in 116 asthmatic children aged 7 to 16 years. Clinical data have been reported previously. To account for the selective withdrawal rate due to pulmonary problems that occurred in the group receiving BA + PL, costs were calculated using 2 approaches: (1) the cumulative cost approach and (2) the patient-year approach. Besides improvements in forced expiratory volume in 1 second (FEV 1) and airway responsiveness expressed as the provocative dose of histamine required to give a 20% fall in FEV 1 (PD 20), the frequency of asthma symptoms and school absenteeism were significantly reduced in the BA + CS group. Annual drug acquisition costs for the group receiving BA + CS were NLG480 higher than for the BA + PL group ($US1 = NLG2.12, 1989 prices). Based on conservative calculations using the cumulative cost approach, annual savings due to reduced healthcare utilisation, excluding the cost of study drugs, by the group receiving BA + CS compared with BA + PL were estimated to be about NLG273 per patient. The incremental cost effectiveness of BA + CS was estimated to be about NLG175 per 10% increase in FEV 1, or somewhat less than NLG10 per symptom-free day gained. The patient-year approach estimated savings due to corticosteroids of about 43% of the costs of BA + PL (95% confidence intervals, 21 to 58%). Savings were larger when the indirect costs that a family incurred during school absenteeism were considered. Addition of an inhaled corticosteroid to an inhaled beta 2-receptor agonist is a cost-effective treatment option that could even result in net healthcare savings.     

Fixed-Dose combination of the inhaled corticosteroid and long-acting beta2-agonist therapy in adults with persistent asthma

Introduction: Asthma is a respiratory condition characterized by airway inflammation, airflow obstruction, and bronchial hyperresponsiveness. The standard treatment of asthma comprises inhaled corticosteroid and beta₂-agonist. Inhaled short-acting-beta₂-agonists have been used as rescue medication for exacerbation. However, long-acting-beta₂-agonists (LABA) used as monotherapy for asthma had been reported for having a safety concern. Consequently, it had been recommended as an add-on treatment to inhaled corticosteroid (ICS) in moderate to severe persistent asthma. The fixed-dose combination (FDC) of ICS and LABA has been approved since the year 2000. Evidences revealed using the combination of these medications is more effective in asthma control.

Areas covered: The rational and phase III onward randomized-controlled studies were reviewed. Sources of evidences were from studies published in Medline until November 2015.

Expert opinion: There are six FDC inhaler regimens approved worldwide. The significant synergistic effects of ICS and LABA in one device are well evidenced. A FDC reduces the daily dosage of ICS and asthma exacerbation. It is safe to use regularly as controller. The efficacy of each individual combination on asthma treatment is generally similar. Clinical experience, ease of use, cost and side effects of medication would guide the clinician’s preferences.     

Concomitant inhaled corticosteroid resensitises cardiac β2-adrenoceptors in the presence of long-acting β2-agonist therapy

Objective: The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac β₂-adrenoceptors in patients receiving regular long-acting β₂-agonists. Methods: Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 μg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic β₂-adrenoceptor responses to inhaled salbutamol (0.8–3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity. Results: There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post- values (407 vs 322 nmol · l⁻¹, but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats · min⁻¹. There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (−0.39 vs −0.48 mmol · l⁻¹). Conclusion: Concomitant therapy with inhaled budesonide resensitised the cardiac β₂-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic β₂-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma. Received: 28 October 1997 / Accepted in revised form: 11 March 1998     

孟鲁司特联合吸入糖皮质激素治疗小儿中度持续哮喘的疗效及机制

目的 观察孟鲁司特联合吸入糖皮质激素治疗小儿中度持续哮喘的临床疗效及探讨孟鲁司特的抗炎机制。方法 采用随机分组的方法，将60例2～5岁的中度持续哮喘患儿分为两组：孟鲁司特4mg／d口服联合吸入布地奈德200ug／d为A组（n=30）、单纯吸入布地奈德200ug／d为B组（n=30）进行3个月的治疗，于治疗开始、治疗第4周和第3个月进行临床评估，同时检测血清半胱氨酰白三烯（CysLTs）和IL-5水平。结果 治疗前，中度持续哮喘患儿血清CysLTs、IL-5水平均明显高于正常组（P〈0．01）；治疗3个月后，A组的患儿哮喘的症状评分、每次发作持续的天数、发作次数和全身使用糖皮质激素的总量均明显低于B组（P〈0．01），同时A组患儿血清CysLTs、IL-5水平较B组显著下降（P〈0．05，P〈0．01），而B组患儿治疗前后血清CysLTs水平差异无统计学意义（P〉0．05）。结论 孟鲁司特联合吸入糖皮质激素可佩著提高中度持续哮喘患儿的疗效，同时减少全身使用糖皮质激素的总量。孟鲁司特能降低中度持续哮喘患儿血清CysLTs、IL-5水平，抑制炎症介质释放，抑制效应可能是孟鲁司特抗哮喘呼吸道炎症的重要机制。     

Risk metrics and cumulative risk assessment methodology for the FQPA

The Food Quality Protection Act (FQPA) of 1996 mandates that the U.S. Environmental Protection Agency consider both aggregate and cumulative risks. Aggregate assessments account for multiple sources and routes of exposure for a single chemical. Cumulative assessments combine exposures to two or more chemicals that share a common mechanism of toxicity. Probabilistic risk assessment methods are described for determining a population's distribution of the dose from exposure and the combination of that exposure characterization with appropriate toxicological information to form a risk assessment. An individual's dose from exposure is characterized as a set of chemical- and route-specific dose profiles over time. For each individual and each chemical and route, a margin of exposure (MOE) is calculated by dividing a toxicologically relevant benchmark dose (e.g., an ED(10)) by the individual's dose from exposure. The set of these MOEs for an individual is combined into the individual's Total MOE. The distribution of the Total MOEs in a population is compared to an Acceptable MOE. Advantages of the Total MOE approach over approaches based on reference doses are discussed. Some general comments on risk metrics are made, and some general guidance for cumulative risk assessments is provided.     

An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers

The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC_0–20) for plasma cortisol and white blood cell (WBC) counts was calculated. Results: The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion: The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.