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In Vitro Determination of Respimat® Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models.

ABSTRACT: BACKGROUND:Aerosol therapy in young children can be difficult. A realistic model based on handling studies and in vitro investigations can complement clinical deposition studies and be used to enable dose-to-the-lung (DTL) predictions. METHODS:Predictions on dose delivery to the lung were based on (1) representative inhalation flow profiles from children enrolled in a Respimat® handling study, (2) in vitro measurement of the fine-particle DTL using mouth-throat models derived from nuclear magnetic resonance/computed tomography (NMR/CT) scans of children, and (3) a mathematical model to predict the tiotropium DTL. Accuracy of the prediction was confirmed using pharmacokinetic (PK) data from children with cystic fibrosis enrolled in a phase 3 clinical trial of tiotropium Respimat with valved holding chamber (VHC). RESULTS:Representative inhalation flow profiles for each age group were obtained from 56 children who successfully inhaled a volume >0.15?L from the Respimat with VHC. Average dimensions of the mouth-throat region for 38 children aged 1-<2 years, 2-<3 years, 3-<4 years, and 4-<5 years were determined from NMR/CT scans. The DTL from the Respimat plus VHC were determined by in vitro measurement and were 5.1±1.1%, 15.6%±1.4%, 17.9%±1.5%, and 37.1%±1.8% of the delivered dose for child models 0-<2 years, 2-<3 years, 3-<4 years, and 4-<5 years, respectively. This provides a possible explanation for the age dependence of clinical PK data obtained from the phase 3 tiotropium trial. Calculated in vitro DTL per body mass (?g/kg [±SD]) were 0.031±0.014, 0.066±0.031, 0.058±0.024, and 0.059±0.029, respectively, compared to 0.046 in adults. Therefore, efficacy of the treatment was not negatively impacted in spite of the seemingly low percentages of the DTL. CONCLUSIONS:We conclude that the combination of real-life inhalation profiles with respective mouth-throat models and in vitro determination of delivered DTL is a good predictor of the drug delivery to children via the Respimat with VHC. The data provided can be used to support data from appropriate clinical trials.

SUBMITTER: Bickmann D

PROVIDER: S-EPMC4739345 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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In Vitro Determination of Respimat<sup>®</sup> Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models.

Bickmann Deborah D Kamin Wolfgang W Sharma Ashish A Wachtel Herbert H Moroni-Zentgraf Petra P Zielen Stefan S

Journal of aerosol medicine and pulmonary drug delivery 20150622 1

<h4>Background</h4>Aerosol therapy in young children can be difficult. A realistic model based on handling studies and in vitro investigations can complement clinical deposition studies and be used to enable dose-to-the-lung (DTL) predictions.<h4>Methods</h4>Predictions on dose delivery to the lung were based on (1) representative inhalation flow profiles from children enrolled in a Respimat<sup>®</sup> handling study, (2) in vitro measurement of the fine-particle DTL using mouth-throat models d ...[more]

PMID: 26098994

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Project description:IntroductionChronic obstructive pulmonary disease (COPD) is a progressive disease requiring maintenance therapy. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report, bronchodilation with long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), administered via inhalers, is currently the mainstay of COPD treatment. Combined LAMA/LABA therapies have been shown to improve patient health status, lung function and breathlessness. Here, we wanted to report patient satisfaction with the Respimat® Soft Mist™ inhaler (SMI).MethodsThis was a pooled analysis of SPIRIT® (NCT02675517) and OTIVACTO® (NCT02719639), two open-label, single-arm, non-interventional studies of physical function in patients with COPD. Patients were treated with tiotropium/olodaterol 5/5 μg for approximately 6 weeks via the SMI. SPIRIT was conducted in Germany; OTIVACTO was conducted in nine European countries. The primary endpoints have been reported previously. Here, we assess patient satisfaction with inhalation and handling, and patient adherence to treatment with the tiotropium/olodaterol SMI in patients with COPD. These were assessed through self-reported questionnaires and physician general assessments.ResultsBaseline data were collected from 9180 patients from the SPIRIT and OTIVACTO studies. The majority of patients were GOLD group A (25.59%) or B (46.12%). After 6 weeks of treatment with tiotropium/olodaterol, 85.78% of patients were 'satisfied' or 'very satisfied' with inhaling from the device, and 84.33% of patients were 'satisfied' or 'very satisfied' with the handling of the inhaler. Treating physicians reported patient adherence as 'high' during the study, with 98.57% of patients regularly using the tiotropium/olodaterol SMI. Furthermore, 95.45% of patients expressed a willingness to continue using the tiotropium/olodaterol SMI at the end of the observation period.ConclusionIn this study, over 9000 patients reported satisfaction with respect to inhalation and handling of the Respimat SMI, and patient adherence was high.Trial registrationClinicalTrials.gov: NCT02675517 (SPIRIT) and NCT02719639 (OTIVACTO).

Project description:IntroductionThe safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO® studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies.MethodsThese were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies.ResultsOf 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.ConclusionOver half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Project description:IntroductionTiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler(®) (18 μg once daily) or Respimat(®) Soft Mist™ inhaler (5 μg once daily). The recent TIOtropium Safety and Performance In Respimat(®) (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium(®) using data from placebo-controlled HandiHaler(®) and Respimat(®) trials.MethodsPooled analysis of adverse event (AE) data from tiotropium HandiHaler(®) 18 μg and Respimat(®) 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler(®) and Respimat(®) trials, both together and separately.ResultsIn the 28 HandiHaler(®) and 7 Respimat(®) trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler(®); 2,440 with Respimat(®)) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler(®) and Respimat(®) pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.ConclusionThis analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler(®) or Respimat(®) (overall and separately) in patients with COPD.

Project description:BackgroundTiotropium, a once-daily long-acting anticholinergic bronchodilator, when administered via Respimat® SoftMist™ inhaler (tiotropium Respimat®) significantly reduces the risk of severe exacerbations and improves lung function in patients with severe persistent asthma that is not fully controlled despite using inhaled corticosteroids (ICS) and long-acting β2-agonists. To further explore the dose-response curve in asthma, we investigated the efficacy and safety of three different doses of tiotropium Respimat® as add-on to ICS in symptomatic patients with moderate persistent asthma.MethodsIn this randomised, double-blind, placebo-controlled, four-way crossover study, patients were randomised to tiotropium Respimat® 5 μg, 2.5 μg or 1.25 μg or placebo Respimat®, once daily in the evening. Each treatment was administered for 4 weeks, without washout between treatment periods. Eligibility criteria included ≥60% and ≤90% of predicted normal forced expiratory volume in 1 second (FEV1) and seven-question Asthma Control Questionnaire mean score of ≥1.5. Patients were required to continue maintenance treatment with stable medium-dose ICS for at least 4 weeks prior to and during the treatment period. Long-acting β2-agonists were not permitted during the treatment phase. The primary efficacy end point was peak FEV1 measured within 3 hours after dosing (peak FEV1(0-3h)) at the end of each 4-week period, analysed as a response (change from study baseline).ResultsIn total, 149 patients were randomised and 141 completed the study. Statistically significant improvements in peak FEV1(0-3h) response were observed with each tiotropium Respimat® dose versus placebo (all P < 0.0001). The largest difference from placebo was with tiotropium Respimat® 5 μg (188 mL). Trough FEV1 and FEV1 area under the curve (AUC)(0-3h) responses were greater with each tiotropium Respimat® dose than with placebo (all P < 0.0001), and both were greatest with 5 μg. Peak forced vital capacity (FVC)(0-3h), trough FVC and FVC AUC(0-3h) responses, versus placebo, were greatest with tiotropium Respimat® 5 μg (P < 0.0001, P = 0.0012 and P < 0.0001, respectively). Incidence of adverse events was comparable between placebo and all tiotropium Respimat® groups.ConclusionsOnce-daily tiotropium Respimat® add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma. Overall, improvements were largest with tiotropium Respimat® 5 μg.Trial registrationClinicalTrials.gov identifier NCT01233284.

Project description:BackgroundTiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups.MethodsTIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial.ResultsThe substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV1 (average 24-120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: -10 [-38, 18] mL for Respimat® 5 μg and, -37 [-65, -9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not.ConclusionsThe TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV1, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction.Trial registrationNCT01126437.

Project description:BackgroundPatients with chronic obstructive pulmonary disease (COPD) show signs of reduced physical activity from the early stages of the disease, impacting morbidity and mortality. Data suggest treatment with tiotropium, a long-acting muscarinic antagonist, and olodaterol, a long-acting ß2-agonist (LABA), as monotherapies and in combination, increases exercise capacity. This study assessed the effects of fixed-dose tiotropium/olodaterol (delivered via Respimat®) on physical function in Global Initiative for Chronic Obstructive Lung Disease A-D patients requiring long-acting dual bronchodilation treatment in a real-world setting.MethodsThis open-label, single arm, noninterventional study measured changes in physical function in COPD patients treated with tiotropium/olodaterol 5/5 μg for approximately 6 weeks (between Visit 1 [baseline] and Visit 2). Primary end point was therapeutic success, defined as a minimum 10-point increase in Physical Functioning Questionnaire (PF-10) score. Secondary end points included change in PF-10 from Visit 1 to Visit 2, the patient's general condition (measured by Physician's Global Evaluation score) at Visit 1 and Visit 2, and patient satisfaction with treatment delivered via the Respimat® device (assessed by Patient Satisfaction Questionnaire) at study end.ResultsTherapeutic success was observed in 51.5% of 1578 patients (95% confidence interval [CI] 49.0, 54.0) after approximately 6 weeks of treatment with tiotropium/olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 11.6 points (95% CI 10.7, 12.6). Patient general condition improved as indicated by a general improvement in scores between visits. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment (82.5%), inhalation (87.5%), and handling of Respimat® (85.2%). One percent of patients reported an investigator-defined drug-related adverse events (AE).ConclusionTiotropium/olodaterol treatment improved physical functioning in COPD patients. An associated increase in patient general condition was observed. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment, inhaling, and handling of the Respimat® device. No unexpected drug-related AE occurred.

Project description:IntroductionPatients with chronic obstructive pulmonary disease (COPD) often report deteriorated functional status and poor health-related quality of life, both core aspects of their overall health status. The study objective was to assess tiotropium/olodaterol Respimat® effects on health and functional status of COPD patients requiring long-acting dual bronchodilation treatment in the real world.MethodsELLACTO was an open-label, observational, prospective study conducted in Greece, measuring changes on health and functional status of COPD patients treated with a fixed dose of tiotropium/olodaterol Respimat® for approximately 6 weeks. The primary endpoint was "therapeutic success" defined as a ≥ 0.4-point decrease in the Clinical COPD Questionnaire (CCQ) score at week 6. Secondary endpoints included absolute changes in the CCQ and the functional subscale CCQ-4 at week 6, patient general condition measured by Physician's Global Evaluation (PGE) score at baseline and week 6, patient satisfaction and preference with Respimat® device (assessed by the abbreviated Patient Satisfaction and Preference Questionnaire (PASAPQ)) at week 6 and treatment continuation with tiotropium/olodaterol Respimat® after the study.ResultsAfter approximately 6 weeks of treatment with tiotropium/olodaterol Respimat®, therapeutic success was achieved by 64.3% of 1332 patients included in the final analysis [95% confidence interval [CI] 62-67]. Mean [standard deviation (SD)] absolute changes in CCQ and CCQ-4 scores at week 6 were - 0.63 (0.635) and - 0.59 (0.714) points, respectively. Patient general condition improved and more than 77.4% of patients were satisfied or very satisfied with the use of the Respimat® device. Among patients previously using the HandiHaler® device (n = 254), 85.4% expressed a preference for Respimat® over 6.7% for HandiHaler®. Most patients (95.7%) were willing to continue treatment with tiotropium/olodaterol Respimat® after the study.ConclusionsTreatment with tiotropium/olodaterol Respimat® led to an improved health status in Greek COPD patients. Most patients also expressed a preference for the Respimat® device and willingness to continue treatment with it.Trial registrationClinicalTrials.gov NCT03419962.

Dataset Information

In Vitro Determination of Respimat® Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models.

Publications

In Vitro Determination of Respimat<sup>®</sup> Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models.

Similar Datasets

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