Thomas D. Bethke

Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. METHODS This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned roflumilast 250 microg (n=576), roflumilast 500 microg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat. FINDINGS 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 microg group, and 124 (22%) from the roflumilast 500 microg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 microg (by 74 mL [SD 18]) and roflumilast 500 microg (by 97 mL [18]) compared with placebo (p<0.0001). Improvement in health-related quality of life was greater with roflumilast 250 microg (-3.4 units [0.6]) and roflumilast 500 microg (-3.5 units [0.6]) than with placebo (-1.8 units [0.8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1.13 (2.37), 1.03 (2.33), and 0.75 (1.89) with placebo, roflumilast 250 microg, and roflumilast 500 microg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study. INTERPRETATION Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.

Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD

Background: Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. Methods: In a crossover study, 38 patients with COPD (mean (SD) age 63.1 (7.0) years, post-bronchodilator forced expiratory volume in 1 s (FEV1) 61.0 (12.6)% predicted) received 500 μg roflumilast or placebo once daily for 4 weeks. Induced sputum samples were collected before and after 2 and 4 weeks of treatment. Differential and absolute cell counts were determined in whole sputum samples. Markers of inflammation were determined in sputum supernatants and blood. Spirometry was performed weekly. Results: Roflumilast significantly reduced the absolute number of neutrophils and eosinophils/g sputum compared with placebo by 35.5% (95% CI 15.6% to 50.7%; p = 0.002) and 50.0% (95% CI 26.8% to 65.8%; p<0.001), respectively. The relative proportion of sputum neutrophils and eosinophils was not affected by treatment (p>0.05). Levels of soluble interleukin-8, neutrophil elastase, eosinophil cationic protein and α2-macroglobulin in sputum and the release of tumour necrosis factor α from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FEV1 improved significantly during roflumilast compared with placebo treatment with a mean difference between treatments of 68.7 ml (95% CI 12.9 to 124.5; p = 0.018). Conclusion: PDE4 inhibition by roflumilast treatment for 4 weeks reduced the number of neutrophils and eosinophils, as well as soluble markers of neutrophilic and eosinophilic inflammatory activity in induced sputum samples of patients with COPD. This anti-inflammatory effect may in part explain the concomitant improvement in post-bronchodilator FEV1.

The New Phosphodiesterase 4 Inhibitor Roflumilast Is Efficacious in Exercise‐Induced Asthma and Leads to Suppression of LPS‐Stimulated TNF‐α Ex Vivo

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo‐controlled, randomized, double‐blind, two‐period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise‐induced asthma. The patients received placebo or roflumilast (500 μg/day) for28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1,14, and 28.FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1,3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)‐stimulated tumor necrosis factor alpha (TNF‐α) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF‐α level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise‐induced asthma. This result was accompanied by a significant reduction of TNF‐α levels ex vivo. Treatment with roflumilast was safe and well tolerated.

Pharmacokinetics of [14C]ciclesonide after oral and intravenous administration to healthy subjects.

BackgroundCiclesonide is a novel inhaled corticosteroid developed for the treatment of asthma.ObjectiveTo investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion. This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation.MethodsIn a randomised crossover study, six healthy male subjects (age range 19–40 years) received single doses of 6.9mg (oral administration) and 0.64mg (intravenous administration) of [14C]ciclesonide, separated by a washout period of at least 14 days. Total radioactivity was determined in whole blood, plasma, urine and faeces. Serum concentrations of ciclesonide and its major metabolite, the pharmacologically active desisobutyryl-ciclesonide (des-CIC), were determined in serum by high-performance liquid chromatography with tandem mass spectrometry detection.ResultsAfter a 10-minute intravenous infusion, the mean half-life for total radioactivity was 45.2 hours. Elimination of des-CIC was fast with a mean elimination half-life of 3.5 hours. After oral administration, the mean half-life for total radioactivity was 27.5 hours. On the basis of a comparison of dose-normalised areas under the curve of total plasma radioactivity versus time, 24.5% of orally administered [14C]ciclesonide was absorbed. The parent compound ciclesonide was not detected in any of the serum samples after oral administration; serum concentrations of des-CIC were mostly near or below the lower limit of quantification. Thus, systemic bioavailability for des-CIC is <1% and the absolute bioavailability of ciclesonide is even less than this. [14C]Ciclesonide showed no retention in red blood cells. The mean cumulative excretion of total radioactivity was almost complete by 120 hours after oral and intravenous administration. Faecal excretion was the predominant route of excretion for total radioactivity after both routes of administration. Single oral and intravenous administration of ciclesonide was well tolerated.ConclusionsBecause of an almost complete first-pass metabolism, ciclesonide is undetectable in serum after oral administration. Thus, any ciclesonide swallowed after oral inhalation does not contribute to systemically available ciclesonide or to its active metabolite. Drug-related metabolites are excreted mainly via the faeces, and overall recovery of administered radioactivity is virtually complete after an extended sample collection period.

Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor

The dose‐proportional, intraindividual, single‐ and repeated‐dose pharmacokinetics of roflumilast, an oral, once‐daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2‐period, 2‐sequence crossover study, 15 subjects received immediate‐release tablets of roflumilast 250 or 500 μg as single (day 1) and as repeated, once‐daily doses for 8 days (days 5–12). Dose‐adjusted point estimates and 90% confidence intervals of test (500 μg)/reference (250 μg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N‐oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N‐oxide. Repeated oral dosing with roflumilast 250 and 500 μg once daily was well tolerated.

Comparison of the efficacy and safety of ciclesonide 160 μg once daily vs. budesonide 400 μg once daily in children with asthma

Ciclesonide is an onsite‐activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 μg (ex‐actuator; nominal dose 200 μg) vs. budesonide 400 μg (nominal dose) in children with asthma. Six hundred and twenty‐one children (aged 6–11 yr) with asthma were randomized to receive ciclesonide 160 μg (ex‐actuator) once daily (via hydrofluoroalkane metered‐dose inhaler and AeroChamber PlusTM spacer) or budesonide 400 μg once daily (via Turbohaler®) both given in the evening for 12 wk. The primary efficacy end‐point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24‐h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non‐inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: −75, 10 ml, p = 0.0009, one‐sided non‐inferiority, per‐protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two‐sided). The effect on the hypothalamic–pituitary–adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one‐sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 μg once daily and budesonide 400 μg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24‐h urinary cortisol excretion compared with children treated with budesonide after 12 wk.

Investigation of a Potential Food Effect on the Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor, in Healthy Subjects

This open, randomized, single‐dose crossover study investigated effects of a high‐fat meal on the pharmacokinetics of roflumilast and its major active N‐oxide metabolite. Twelve healthy subjects received oral roflumilast 500 μg (2 × 250 μg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N‐oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC0‐last, AUC0‐∞, and Cmax of both compounds. After the meal, roflumilast Cmax (PE, 0.59; 90% CI, 0.49‐0.70) was modestly reduced; N‐oxide Cmax (PE, 0.95; 90% CI, 0.90‐1.01) was unchanged. Roflumilast tmax was delayed in fed state (2.0 ± 0.4 hours) versus fasted state (1.0 ± 0.2 hours); N‐oxide tmax was unaltered. No significant food effect on roflumilast AUC0‐last (PE, 1.04; 90% CI, 0.90‐1.21), AUC0‐∞ (PE, 1.12; 90% CI, 1.00–1.25), and respective N‐oxide AUCs (PE, 0.91; 90% CI, 0.79‐1.04; PE, 0.99; 90% CI, 0.92‐1.06) occurred. Because roflumilast N‐oxide is the major contributor to roflumilasts overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.

Equivalent Pharmacokinetics of the Active Metabolite of Ciclesonide With and Without Use of the AeroChamber Plus™ Spacer for Inhalation

BackgroundCiclesonide is an inhaled corticosteroid that provides safe and effective control of persistent asthma. Ciclesonide is administered as an aerosol solution in a metered-dose inhaler, using hydrofluoroalkane-134a as a propellant. It is activated in the lung to form its only active metabolite, desisobutyryl-ciclesonide (des-CIC). A spacer may be used in combination with the hydrofluoroalkane metered-dose inhaler (HFA-MDI) to maintain inhaled corticosteroid delivery to the lung in patients with poor inhalation technique.ObjectiveTo determine if the pharmacokinetics of des-CIC and ciclesonide are altered when a spacer is used for ciclesonide inhalation.MethodsA randomised, open-label, 2-period crossover, single-center pharma-cokinetic study was conducted in 30 patients with asthma (forced expiratory volume in 1 second ≥70% predicted). A single dose of ciclesonide (320μg exactuator; equivalent to 400μg ex-valve) was administered via the HFA-MDI with and without an AeroChamber Plus™ spacer (Trudell Medical International, London, ON, Canada). Serum concentrations of ciclesonide and des-CIC were measured before inhalation and at various intervals until 14 hours after treatment using high-performance liquid chromatography with tandem mass spectrometric detection.ResultsThe pharmacokinetic properties of the active metabolite, des-CIC, were equivalent after inhalation of ciclesonide with and without the AeroChamber Plus™ spacer. Point estimates and 90% confidence intervals (CIs) for the ratio of des-CIC pharmacokinetic properties in the presence or absence of a spacer were within the conventional bioequivalence range of 0.80–1.25 (area under the serum concentration time curve from time zero to infinity 0.96 [0.85, 1.07]; peak serum concentration 1.05 [0.94, 1.18]; elimination half-life 1.04 [0.92, 1.18]). Furthermore, there was no relevant difference in the point estimate and 90% CI of the difference of the time to reach peak serum concentration of des-CIC with or without a spacer.ConclusionThe AeroChamber Plus™ spacer did not influence the pharmacokinetics of the pharmacologically active des-CIC. Thus, systemic exposure to the active metabolite is similar when ciclesonide is inhaled with or without a spacer. Furthermore, these results are indicative of comparable lung deposition of ciclesonide in both the presence and absence of a spacer.

The Oral, Once-Daily Phosphodiesterase 4 Inhibitor Roflumilast Lacks Relevant Pharmacokinetic Interactions With Inhaled Budesonide

This open‐label, randomized, 3‐period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 μg, once daily, orally inhaled budesonide 800 μg, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and roflumilast N‐oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady‐state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of roflumilast, roflumilast N‐oxide, and budesonide after coadministration of roflumilast and budesonide were similar to those after mono‐treatment. Compared with budesonide and roflumilast mono‐treatments, slightly lower maximum serum/plasma concentration (Cmax) and area under the curve (AUC) values of roflumilast N‐oxide and budesonide (ranging from −8% to −16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for roflumilast AUC (0.80, 1.25) and Cmax (0.70, 1.43) and for roflumilast N‐oxide and budesonide AUC and Cmax (all 0.67, 1.50). Coadministration of roflumilast and budesonide did not alter the steady‐state disposition of each other and did not affect safety and tolerability of either drug.