Evaluation of clinical trials by Ethics Committees in Germany--results and a comparison of two surveys performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa).

OBJECTIVE: The objective of this project was to evaluate the quality and quantity of initial applications for a clinical trial according to § 7 of the German Good Clinical Practice (GCP) ordinance (German: GCP-Verordnung, GCP-V), the quality of evaluations of those applications by Ethics Committees (ECs)/Investigational Review Boards (IRBs) in Germany as well as the pattern of EC objections in their reasoned opinions (vote). In order to identify a change over time, the results of the present survey were also compared with a survey performed in 2008. METHODS: Based on reasoned opinions issued by the respective EC in charge of the coordinating principle investigator (coordinating EC) in 2011, a written survey among members of the German Association of Research-Based Pharmaceutical Companies (vfa) was conducted in 2012. The answers to the questionnaire were analyzed descriptively. Since the data set collected in 2011 was structurally identical with the data set gained in 2007 both surveys were compared. RESULTS: Of the 24 companies represented on the vfa Clinical Research/Quality Assurance Subcommittee, 75% (18) took part in the survey. Survey evaluation was based on a total of 251 applications of these 18 companies submitted to 43 ECs. These account for about 21% of 1,214 applications for authorization of commercial and non-commercial phase I-IV clinical trials submitted to the regulatory authorities (BfArM and PEI) in 2011. In comparison to 2007, a lower amount of applications (n=251 in 2011 vs. n=288 in 2007) was submitted to a slightly higher number of ECs (43 in 2011 vs. 40 in 2007). The amount of objections increased by 21% from 1,299 (2007) to 1,574 (2011) resulting in an average of 4.5 (2007) vs. 6.3 (2011) objections per application. Overall, the analysis of both formal and content related objections revealed almost the same pattern as in the previous survey. In total, the most frequent objections applied to the patient information and consent form followed in descending order by trial protocol content, miscellaneous, other application documents pursuant to § 7 (2) and (3) GCP-V, formal deficiencies pursuant to § 8 (1) GCP-V, and investigator and site qualifications. A trend towards a slightly increased rate of objections concerning patient information and consent form (+4%) and a minimal decrease in objections concerning investigator and site qualifications (-2%) was observed. As in 2007, about 1 in 6 applications was still incomplete with formal objections. Whilst the proportion of study applications with objections related to the patient information and consent form (+7.2%), the trial protocol content (+11.6%), and documents according to § 7 (2) and (3) GCP-V (+11.8%) increased in 2011 compared to 2007, the amount of study applications with objections related to the investigator and site qualifications decreased by 6.3%. CONCLUSIONS: The majority of findings with respect to quantity, quality and main focus of objections reported in the first survey in 2008 were also found in 2012, indicating a shared understanding of applicable measures and criteria by sponsors and ECs on how to ensure patient rights and well-being, data integrity, and high quality documentation in clinical trials.

Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults.

Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with roflumilast under steady-state conditions. Sixteen healthy male and female adults were randomly assigned in an open-label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with roflumilast. Concomitant medication with digoxin did not significantly affect steady-state pharmacokinetics of either roflumilast or its active metabolite roflumilast N-oxide. Roflumilast is not an inhibitor of P-gp. No safety or tolerability concerns were detected with coadministration of roflumilast and digoxin.

Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics.

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties.

Use of recombinant human parathyroid hormone(1-84) in patients with postmenopausal osteoporosis: a prospective, open-label, single-arm, multicentre, observational cohort study of the effects of treatment on quality of life and pain--the PROPOSE study.

BACKGROUND AND OBJECTIVE: Osteoporosis is a progressive bone disorder. Its medical therapy typically involves calcium, vitamin D and antiresorptive drugs. The anabolic parathyroid hormones (PTHs) represent a major advance since they stimulate new bone formation. Two forms of recombinant human PTH (rhPTH) have been evaluated: the 34-amino acid fragment rhPTH(1-34) and the intact 84-amino acid form rhPTH(1-84), the latter being marketed as Preotact®. Osteoporosis leads to increased bone fragility and susceptibility to fracture. Additionally, the disease is often accompanied by pain and a reduced quality of life (QOL). These aspects have rarely been addressed in previously published studies of PTH, which have instead focused on bone density and fractures. The aim of the present study was to evaluate therapy with rhPTH(1-84) in the treatment of osteoporosis in postmenopausal women under everyday practice conditions with emphasis on patients' QOL and pain. METHODS: The study was performed as a prospective, open-label, single-arm, multicentre, observational cohort study that included postmenopausal women in whom treatment with rhPTH(1-84) was newly initiated. Patients were to be treated with rhPTH(1-84) for 12 months at a dose of 100 µg, administered once daily as a subcutaneous injection. The primary efficacy endpoint was the total score on the Quality of Life Questionnaire of the European Foundation for Osteoporosis, 41-item version (QUALEFFO-41). Secondary efficacy criteria were QUALEFFO-41 subscale scores, patients' assessments of pain on visual analogue scales (range 0-100), and performance on the chair rising test. RESULTS: 112 patients were included in the safety and in the intent-to-treat (ITT) efficacy analyses. Sixty-six patients finished the 1-year period (per-protocol group). All ITT patients were female with a mean age of 72 years and a mean duration of osteoporosis of 73 months. During the study, all QUALEFFO-41 scales improved significantly: in the ITT group, the mean total score improved from 49.8 to 41.3 points. In the ITT population, mean pain at rest improved significantly by about 20% and mean pain on movement by about 36%. When patients who took at least one dose of pain medication were compared with those who took no pain medication during the study, it was evident that pain reduction did not occur only as a result of taking pain medication: use of rhPTH(1-84) was associated with a similar pain reduction in both subgroups. The most frequent adverse events (AEs) were hypercalcaemia (12.5% of patients) and nausea and vomiting (10.7% of patients). AEs caused 16% of patients to discontinue during the 12-month study period. CONCLUSION: This 12-month study carried out in a typical sample of postmenopausal women with osteoporosis showed that treatment with rhPTH(1-84) is safe. The present study, which is one of the first to investigate QOL and pain during PTH treatment systematically, also showed that rhPTH(1-84) improves QOL and reduces pain, thereby reducing the burden of osteoporotic symptoms for patients. These results, however, need to be verified in a controlled clinical trial. [ClinicalTrials.gov Identifier: NCT00515593].

Efficacy and safety of ciclesonide in the treatment of 24,037 asthmatic patients in routine medical care.

BACKGROUND: The efficacy and safety profile of ciclesonide (CIC) in the treatment of asthma was evaluated in a large patient population in a real-life setting in Germany. METHODS: 24,037 patients with persistent mild/moderate bronchial asthma were enrolled into three observational studies with identical design. Data were pooled and analyzed. Patients received ciclesonide (160 µg/day) and were observed for 3 months. FEV(1), PEF, NO, asthma episodes, use of rescue medication and adverse drug reactions (ADR) were recorded. RESULTS: Mean (95% CI) FEV(1) significantly increased from 80.7 [80.5; 80.9]% of predicted at baseline to 90.1 [89.9; 90.2]% after 3 months (n = 20,297), mean PEF significantly increased from 338 [335; 340] l/min to 392 [390; 395] l/min (n = 8100). NO was significantly reduced from 53.6 [51.8; 55.4] ppb to 26.2 [25.2; 27.1] ppb (n = 971). The percentage of patients with daily symptoms declined from 24.3% to 1.9%, night-time symptoms from 13.3% to 1.3%, and ß(2)-agonists use from 26.9% to 8.8%. ADRs were reported by 51 patients (0.2%). Most frequent ADRs were: dysphonia (n = 11), cough (n = 10), dyspnoea, throat irritation, and oral candidiasis (n = 5 each). 46 patients terminated the study prematurely, 41 due to ADR and 5 due to unknown/missing reason. One patient died due to cardiac failure (no causal relation). CONCLUSION: These observational studies under real-life conditions support findings from controlled clinical studies regarding efficacy and tolerability of ciclesonide in patients with mild to moderate bronchial asthma. No unexpected ADRs were detected.

Results of a survey on applied quality standards in non-interventional studies among the members of the German Association of Research-based Pharmaceutical Companies.

After the regulatory approval has been obtained, epidemiological studies are acknowledged scientific medical research methods for a new drug which provide additional knowledge about routine application of the drug in clinical daily routine. These studies are performed according to the recommendations of both international and national expert associations, the recommendations of the higher federal authorities in Germany and according to the recommendations of the associations of the pharmaceutical industry. Two surveys among the member companies of the Association of Research-based Pharmaceutical Companies investigated the status of the implementation of the recommendations in the years 2008 and 2010 and compared the results with each other. It could be shown that these recommendations were implemented successfully and were fully adhered to during the conduct of non-interventional studies in Germany. The recommendations define a quality standard which justifies a high level of confidence in the validity of the data collected and the results from these investigations.

Chronopharmacology of roflumilast: a comparative pharmacokinetic study of morning versus evening administration in healthy adults.

The human circadian system is known to affect the pharmacokinetics and pharmacodynamics of several classes of respiratory disease medications. The current study involving 16 healthy adults investigated if the time-of-day of dosing of roflumilast, a novel phosphodiesterase-4 inhibitor, affects its pharmacokinetics. The rate of drug absorption (t(max): 1.50 versus 2.00 h) and peak concentration at t(max) (C(max): 3.79 versus 3.06 µg/L) was slightly greater with morning than evening administration, but without clinical significance. The extent of drug absorption (AUC) and drug elimination (t(1/2)) did not differ between the two dosing times. The pharmacokinetics of the active main metabolite, roflumilast N-oxide, also was not affected by the time of drug administration. Finally, the safety and tolerability of roflumilast did not differ between the two different times of administration.

Effects of multiple-dose esomeprazole and pantoprazole on diazepam pharmacokinetic profile and pharmacodynamic effects on cognitive and psychomotor function in healthy volunteers.

A randomized, double-blind, 2-way crossover trial of 24 healthy volunteers investigated the influence of esomeprazole (CAS 119141-88-7) and pantoprazole (CAS 102625-70-7), both 1 x 40 mg orally for 11 days, on the pharmacokinetics and pharmacodynamics of diazepam (CAS 439-14-5). Single-dose intravenous diazepam 0.1 mg/kg was administered on day 6. Blood sampling for pharmacokinetic assessment was conducted 0-120 h post diazepam application and data were analyzed using a model-independent approach and ANOVA. Pharmacodynamic parameters were assessed by an oculodynamic test and auditory evoked potentials 0-10 h post diazepam application. Data were analyzed using a linear mixed regression model. The AUC of diazepam was increased by 28.0%, Cmax by 31.4% and t1/2 by 41.1% in the esomeprazole vs. pantoprazole group. Myogenic parameters such as angular velocity of saccadic eye movements and complex choice reaction time were impaired with esomeprazole when compared to pantoprazole after diazepam administration (P < 0.0028) at 4-6 h. The sedation parameter microsleep doubled (2.6 vs. 1.1%; P < 0.0073). No differences in auditory evoked potentials were observed. In conclusion, it cannot be ruled out that a relevant pharmacodynamic interaction between diazepam and esomeprazole may occur when both drugs are concomitantly administered. Pantoprazole may provide a higher safety profile.

Single-dose pharmacokinetics of roflumilast in children and adolescents.

Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of roflumilast and roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (100-microg dose in period 1, 250-microg dose in period 2) separated by a washout period. Plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using standard noncompartmental methods and compared between study groups and within the entire cohort. Roflumilast was well tolerated. Linear relationships were evident for dose and area under the plasma drug concentration-time curve extrapolated to infinity for both roflumilast (r(2) = 0.36, P < .01) and roflumilast N-oxide (r(2) = 0.39, P < .01). With the exception of dose-normalized maximum plasma concentration (mean 1.1 and 0.8 microg/L per 1 microg/kg dose for adolescents and children, respectively), pharmacokinetic parameters for roflumilast and roflumilast N-oxide were not different between age groups and were similar to adults.

Comparison of the efficacy and safety of ciclesonide 160 microg once daily vs. budesonide 400 microg 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 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg 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 microg once daily and budesonide 400 microg 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.

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 mug, once daily, orally inhaled budesonide 800 mug, 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 (C(max)) 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 C(max) (0.70, 1.43) and for roflumilast N-oxide and budesonide AUC and C(max) (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.

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 (FEV(1)) 61.0 (12.6)% predicted) received 500 microg 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 alpha(2)-macroglobulin in sputum and the release of tumour necrosis factor alpha from blood cells were significantly reduced by roflumilast compared with placebo treatment (p<0.05 for all). Post-bronchodilator FEV(1) 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 FEV(1).

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 microg 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 microg)/reference (250 microg) 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 microg once daily was well tolerated.

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 microg (2 x 250 microg) 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 AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (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 roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.

Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.

Equivalent pharmacokinetics of the active metabolite of ciclesonide with and without use of the AeroChamber Plus spacer for inhalation.

BACKGROUND: Ciclesonide 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. OBJECTIVE: To determine if the pharmacokinetics of des-CIC and ciclesonide are altered when a spacer is used for ciclesonide inhalation. METHODS: A randomised, open-label, 2-period crossover, single-center pharmacokinetic study was conducted in 30 patients with asthma (forced expiratory volume in 1 second > or = 70% predicted). A single dose of ciclesonide (320 microg ex-actuator; equivalent to 400 microg 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. RESULTS: The 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. CONCLUSION: The 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.

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.

Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metered-dose inhaler in healthy subjects.

OBJECTIVE: Inhaled corticosteroids may cause oropharyngeal side effects if deposited in the oropharynx in active form. Ciclesonide, an inhaled corticosteroid with low glucocorticoid receptor affinity, is activated primarily in the lung by esterases to an active metabolite, desisobutyryl-ciclesonide (des-CIC), with high glucocorticoid receptor affinity. We studied oropharyngeal deposition of ciclesonide, des-CIC, and budesonide. METHODS: In an open-label, randomized, two-treatment (administered in sequence), five-period study, 18 healthy subjects received 800 microg (ex-valve) inhaled ciclesonide via a hydrofluoroalkane-pressurized, metered-dose inhaler followed by 800 microg budesonide (Pulmicort) by a chlorofluorocarbon-pressurized, metered-dose inhaler (four puffs of 200 microg each, ex-valve) or vice versa. Oropharyngeal cavity rinsing was performed immediately, or 15, 30, 45, or 60 min after inhalation (one rinsing per study period), and the solutions were analyzed using liquid chromatography with tandem mass spectrometric detection. RESULTS: Ciclesonide and budesonide were detected in most oropharyngeal wash samples. Maximal concentration of each inhaled corticosteroid was reached immediately post-inhalation; maximal concentrations of ciclesonide and des-CIC were 30% and 0.67%, respectively, of budesonide. Oropharyngeal deposition of ciclesonide and budesonide decreased rapidly within 15 min post-inhalation, and less rapidly thereafter. Less than 10% of the residual ciclesonide in the oropharynx was converted to des-CIC. The molar dose-adjusted amount of des-CIC was 4% of budesonide (P < 0.0001). There were no significant adverse events. CONCLUSION: Oropharyngeal deposition of des-CIC was more than one order of magnitude lower than that of budesonide when administered by the respective metered-dose inhalers. This may explain the low frequency of oropharyngeal side effects of ciclesonide in clinical studies.

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

BACKGROUND: Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. OBJECTIVE: To 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. METHODS: In a randomised crossover study, six healthy male subjects (age range 19-40 years) received single doses of 6.9 mg (oral administration) and 0.64 mg (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. RESULTS: After 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. CONCLUSIONS: Because 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.