desisobutyrylciclesonide and Asthma

Inhaled corticosteroids are used as one of the first-line drug therapy in patients with asthma. However, their long-term use is associated with various oropharyngeal and systemic side and adverse effects. Design of pro-soft drug is one of the strategies, which was adopted in the design of ciclesonide for mitigation of side effects usually observed with the use of inhaled corticosteroids. Ciclesonide, a pro-soft drug, is converted to an active metabolite desisobutyryl-ciclesonide in the lungs. The anti-inflammatory effect of desisobutyryl-ciclesonide is much higher than ciclesonide, and therefore, the local effect of the metabolite is higher with lower systemic side effects. Ciclesonide has favorable pharmacokinetic and pharmacodynamic properties as inhaled corticosteroid including low oral bioavailability, high plasma protein binding and rapid systemic clearance, high pulmonary deposition and distribution and long pulmonary residence duration. These advantageous properties make ciclesonide a very effective treatment option with low side effects. Various clinical studies support safety and efficacy of ciclesonide use in mild, moderate, and severe asthma patients.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Biological Availability; Drug Design; Humans; Lung; Pregnenediones; Protein Binding; Tissue Distribution

Ciclesonide (CIC) is a novel inhaled corticosteroid (ICS) approved by US Food and Drug Administration for the treatment of persistent asthma, available as a pressurized metered-dose inhaler in two strengths, 80 mcg/activation and 160 mcg/activation. Ciclesonide is a corticosteroid with unique pharmacological profile including a high degree of serum protein binding, a low oral bioavailability and rapid systemic elimination. Ciclesonide is a prodrug metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. It has shown to improve pulmonary functions, reduce the need for oral corticosteroids (OCSs) and cause lesser suppression of the hypothalamic-pituitary-adrenal axis in asthmatic patients. Clinical efficacy studies suggest that Ciclesonide is superior to placebo and is at least as effective as several active comparators with an improved therapeutic margin thereby improving the therapeutic outcome in patients of asthma.

Topics: Administration, Inhalation; Anti-Asthmatic Agents; Asthma; Biological Availability; Humans; Metered Dose Inhalers; Pregnenediones; Prodrugs; Protein Binding; Receptors, Glucocorticoid

Asthma is a chronic inflammatory disease of the airways, and inhaled corticosteroids (ICSs) are recommended as first-line therapy for persistent asthma of all severities. Ciclesonide is a novel ICS, which is administered as an aerosol solution in a metered-dose inhaler, using hydrofluoroalkane-134a as a propellant. Because of the high respirable particle fraction, high pulmonary deposition is obtained in patients, which constitutes the basis of effective therapeutic action. The parent compound, ciclesonide, is pharmacologically inactive and is activated in the target organ, the lung, to form its only pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC). Low oral deposition combined with minimal formation of des-CIC in the oropharynx may minimize the typical oropharyngeal adverse events associated with ICSs. Low oral bioavailability, rapid clearance and high protein binding reduce pharmacologically relevant systemic exposure. The unique pharmacokinetic and pharmacodynamic profile of ciclesonide offers a rationale that supports the favourable risk-benefit profile observed in clinical trials in patients with persistent asthma.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Asthma; Drug Interactions; Humans; Lung; Molecular Structure; Oropharynx; Pregnenediones; Protein Binding; Radionuclide Imaging

Inhaled corticosteroids, such as fluticasone propionate (FP) and ciclesonide (CIC), are commonly used for the treatment of asthma. The objectives of this study were to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of FP and a pharmacologically active metabolite of CIC (desisobutyryl-ciclesonide [Des-CIC]) using a nonlinear mixed-effects modeling approach, to investigate selected covariate effects on PK and PD parameters of FP and Des-CIC, and to assess the systemic effects of FP and CIC on serum cortisol suppression in patients with persistent asthma. This was a randomized, double-blind, placebo-controlled, double-dummy, 5-period, crossover, multicenter clinical study. A total of 32 patients were enrolled and given basic asthma medication (salmeterol 50 µg twice per day [BID] and CIC 160 µg daily in the evening) through the entire study. During crossover periods, patients were given placebo or CIC 160 µg BID (ex actuator), CIC 320 µg BID (ex actuator), FP 220 µg BID (ex actuator), or FP 440 µg BID (ex actuator). The FP and Des-CIC PK were described using a 1-compartment and a 2-compartment linear model with first-order absorption process. The FP population PK parameter estimates of the first-order rate constant, relative clearance, and volume of distribution were 4.07 1/h, 890 L/h, and 9800 L, respectively. The Des-CIC PK parameter estimates of the first-order absorption rate constant were 2.63 1/h, clearance 202 L/h (non-CIC treatment) or 271 L/h (CIC treatment), and volume of distribution 947 L. Gender was a significant covariate on the maximum cortisol release rate (male, 3440 µg/h; female, 4310 µg/h). The CIC showed the least serum cortisol suppression of the tested dosing regimens.

Topics: Administration, Inhalation; Adult; Albuterol; Androstadienes; Anti-Allergic Agents; Area Under Curve; Asthma; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; Half-Life; Humans; Hydrocortisone; Male; Middle Aged; Pregnenediones; Salmeterol Xinafoate; Sex Factors

To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects.. 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 microg (ex-actuator, equivalent to 1,600 microg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry.. There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC(0 - inf)) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t1/2) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups.. After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.

Topics: Administration, Inhalation; Adult; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Area Under Curve; Asthma; Case-Control Studies; Dose-Response Relationship, Drug; Female; Half-Life; Headache; Humans; Male; Middle Aged; Pregnenediones

Ciclesonide is a novel inhaled corticosteroid that is converted in the lungs to its active metabolite, desisobutyryl-ciclesonide (des-CIC). The aim of this study was to compare the deposition of ciclesonide, as well as its conversion to des-CIC, in the oropharyngeal cavity with fluticasone propionate (FP) following inhalation via hydrofluoroalkane-propelled metered-dose inhalers (HFA-MDIs). Eighteen asthmatics inhaled ciclesonide 800 microg followed by FP 1000 microg or vice versa in an open, randomized, 2-treatment, 2-sequence study design. The oropharynx was washed out immediately and at 15, 30, 45, and 60 minutes after inhalation. Samples were analyzed for ciclesonide, des-CIC, and FP using liquid chromatography with tandem mass-spectrometric detection. Concentration-time curves and area under the concentration-time curve (AUC) were calculated for each drug. Ciclesonide and FP were recovered in almost all samples. Within 60 minutes after inhalation, the amounts of both ciclesonide and FP decreased sharply, and low residual levels were detected after 30 minutes. des-CIC was detected in relatively low concentrations, with maximum concentration 30 minutes following inhalation. The AUC(0-60 min) for ciclesonide (250.4 nmol x h/L) and des-CIC (37.8 nmol x h/L) were found to be significantly lower compared with FP (636.2 nmol.h/L, P < .001). Approximately 50% less ciclesonide and 90% less metabolite were present in the oropharynx compared with FP. Less than 20% of the residual ciclesonide in the oropharynx was metabolized to des-CIC. These findings indicate that oropharyngeal deposition of ciclesonide is only half that of FP following inhalation from an HFA-MDI. Furthermore, there is little activation of ciclesonide to its active metabolite in the oropharynx, suggesting a decreased likelihood of inhaled ciclesonide-associated oropharyngeal side effects.

Topics: Administration, Inhalation; Adult; Androstadienes; Area Under Curve; Asthma; Chromatography, Liquid; Cough; Drug Administration Schedule; Ethanol; Female; Fluticasone; Humans; Male; Mass Spectrometry; Metered Dose Inhalers; Oropharynx; Pregnenediones; Solutions; Therapeutic Irrigation; Time Factors

Ciclesonide is an inhaled corticosteroid (delivered via a hydrofluoroalkane metered-dose inhaler) that is converted to an active metabolite, desisobutyryl-ciclesonide, in the lung, thereby minimising effects on endogenous cortisol. In two 12-week, randomised studies in patients with asthma, ciclesonide 80 or 320 microg once daily was at least as effective as budesonide 400 microg/day at increasing forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline; ciclesonide 320 microg daily was significantly more effective than budesonide 400 microg once daily in one study. In a randomised, double-blind study in patients with asthma controlled with high-dosages of inhaled corticosteroids, FEV(1) and FVC decreased significantly from baseline at 12 weeks in patients receiving ciclesonide 320 microg daily or budesonide 400 microg daily; peak expiratory flow values decreased significantly only in patients receiving budesonide. Inhaled ciclesonide 80 or 320 microg daily improved asthma symptom scores and decreased the use of rescue medication by a similar, significant amount to budesonide 400 microg/day in two 12-week studies. Inhaled ciclesonide was generally well tolerated in patients with asthma. Ciclesonide did not suppress biochemical markers of adrenal function in 52-week studies. The long-term (>52 weeks) systemic effects of ciclesonide remain unknown.

Topics: Administration, Inhalation; Adult; Asthma; Budesonide; Drug Administration Schedule; Esterases; Half-Life; Humans; Injections, Intravenous; Metered Dose Inhalers; Pregnenediones; Time Factors

The development of more efficient drug delivery devices for ciclesonide inhalation products requires an ultrasensitive bioanalytical method to measure systematic exposure of ciclesonide (CIC) and its active metabolite desisobutyryl-ciclesonide (des-CIC) in humans.. Serum sample was extracted with 1-chlorobutane. A reversed-phase liquid chromatography coupled with atmospheric pressure photoionization-tandem mass spectrometry (LC-APPI-MS/MS) method was used for quantification of 1-500 pg/mL for both analytes in a 0.500-mL serum. The analysis time was 4.7 min/injection. CIC-d11 and des-CIC-d11 were used as the internal standards.. Calibration curves showed good linearity (r2 > 0.99) for both analytes. This novel method was precise and accurate with interassay precision and accuracy of all within 9.6% CV and ± 4.0% bias for regular QC samples. Extraction recovery was approximately 85% for both analytes. Serum samples are stable for 3 freeze-thaw cycles, 24 h at bench top, and up to 706 days at both -20 °C and -70 °C. This method was successfully used to support a pharmacokinetic (PK) comparison between the inhalation suspensions and an inhalation aerosol of ciclesonide in healthy participants. The method robustness was also supported by the good incurred sample reanalysis reproducibility.. APPI, a highly selective and sensitive ionization source, made possible for quantifying CIC and des-CIC with a lower limit of quantification (LLOQ) of 1 pg/mL in human serum by LC-MS/MS. A 10-fold sensitivity improvement from the most sensitive reported method (LLOQ, 10 pg/mL) is essential to fully characterize the PK profiles of CIC and des-CIC in support of the clinical development of the ciclesonide-related medications for patients.

Topics: Administration, Inhalation; Asthma; Chromatography, Liquid; Dimensional Measurement Accuracy; Drug Delivery Systems; Drug Elimination Routes; Glucocorticoids; Half-Life; Humans; Nebulizers and Vaporizers; Pregnenediones; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

To examine the deposition and pharmacokinetics of ciclesonide administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) in patients with asthma.. Twelve patients with mild asthma (FEV1, 95% predicted) inhaled a single dose of 99mtechnetium (Tc)-ciclesonide 320 microg ex-actuator (400 microg ex-valve). Deposition of ciclesonide in the lung and oropharynx was quantified using two-dimensional (2D)-gamma scintigraphy. Three-dimensional single photon emission computed tomography (3D SPECT) was used to assess the regional distribution of ciclesonide in the lung. The pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC), were determined by liquid chromatography-tandem mass spectrometry. Ciclesonide and des-CIC concentrations were determined in mouth-rinsing solutions.. 2D-gamma scintigraphy indicated that ciclesonide deposition was higher in the whole lung (52%) than in the oropharynx (32.9%). Furthermore, 3D SPECT revealed that ciclesonide deposition within the lungs was highest in the peripheral regions that contain the small airways and alveoli. The pharmacokinetic profile of Tc-labeled ciclesonide and des-CIC was similar to that obtained after inhalation of non-labeled formulations in previous studies. Des-CIC accounted for 14.9% of the total molar concentration of ciclesonide/des-CIC in mouth-rinsing solutions obtained between 7 and 12min after inhalation.. Inhalation of ciclesonide via HFA-MDI results in high pulmonary deposition, especially in the peripheral regions of the lung. High pulmonary deposition contributes to ciclesonide's ability to maintain lung function and control symptoms in patients with asthma. Deposition and activation of ciclesonide in the oropharynx is low, consistent with previous reports of low oropharyngeal deposition and a reduced incidence of local side effects in patients receiving ciclesonide therapy.

Topics: Administration, Inhalation; Adult; Asthma; Bronchodilator Agents; Cohort Studies; Female; Gas Chromatography-Mass Spectrometry; Humans; Lung; Male; Metered Dose Inhalers; Middle Aged; Oropharynx; Pregnenediones; Technetium; Tomography, Emission-Computed, Single-Photon