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Pooled analysis of tiotropium Respimat® pharmacokinetics in cystic fibrosis
Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
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Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Pooled analysis of tiotropium Respimat® pharmacokinetics in cystic fibrosis Ashish Sharma a, *, David E. Geller b, 1, Petra Moroni-Zentgraf c, Sabine Kattenbeck d, Marion Schmid a, Katja Boland a, Barbara Rapp a, Michael W. Konstan e, Felix Ratjen f, J. Stuart Elborn g, Paul Koker h a
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, Biberach 88400, Germany Florida State University College of Medicine, Orlando, FL, USA Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, Ingelheim 55216, Germany d Boehringer Ingelheim GmbH, Ingelheim, Binger Str. 173, Ingelheim 55216, Germany e Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, USA f Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto M5G 1X8, Ontario, Canada g Centre for Infection and Immunity, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK h Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06776, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2014 Received in revised form 12 August 2014 Accepted 15 August 2014 Available online 24 August 2014
Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat® in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat® across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and 18 years had similar tiotropium plasma concentrations (geometric mean C0.083,ss,norm: 2.22 pg/mL/mg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe0e4,ss: 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Tiotropium Respimat® inhaler Pharmacokinetics Cystic fibrosis
1. Introduction Cystic fibrosis (CF) is associated with airway obstruction, in part due to airway reactivity [1,2]. Around 90% of CF deaths are attributed to respiratory failure secondary to the combined effects of airway obstruction, infection, and inflammation [3]. Current
* Corresponding author. Tel.: þ49 7351 54 94779; fax: þ49 7351 54 90170. E-mail addresses: [email protected] (A. Sharma), [email protected] (D.E. Geller), [email protected] (P. Moroni-Zentgraf), sabine.kattenbeck@boehringer-ingelheim. com (S. Kattenbeck), [email protected] (M. Schmid), [email protected] (K. Boland), [email protected] (B. Rapp), [email protected] (M.W. Konstan), felix. [email protected] (F. Ratjen), [email protected] (J.S. Elborn), paul.koker@ boehringer-ingelheim.com (P. Koker). 1 Florida State University College of Medicine at time of study. Currently employed by AbbVie Inc., North Chicago, IL, USA. http://dx.doi.org/10.1016/j.pupt.2014.08.004 1094-5539/© 2014 Elsevier Ltd. All rights reserved.
treatment regimens are complex and burdensome for patients with CF [4]. More than 80% of patients with CF are prescribed short- or long-acting bronchodilators [5], mostly b2-adrenergic agonists, although none of these agents are approved by regulatory agencies for use in CF, and their therapeutic benefit has not been clearly defined [6]. Tiotropium is a long-acting anticholinergic bronchodilator administered by inhalation and approved for maintenance treatment in patients with chronic obstructive pulmonary disease (COPD) [7,8]. Tiotropium, delivered either by the multidose Respimat® Soft Mist Inhaler™ (SMI) (Boehringer Ingelheim, Ingelheim, Germany) or the HandiHaler® (Boehringer Ingelheim, Ingelheim, Germany), can provide 24-h sustained improvement in lung function and reduce hyperinflation, incidence of dyspnea, and the risk of exacerbations, resulting in an improved health-related quality of life [7e15]. Tiotropium has recently been systematically studied in a clinical program consisting of 3 placebo-controlled, multicenter trials of
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tiotropium Respimat® [16e19] that investigated the safety, efficacy, and tolerability of inhaling single and multiple doses of tiotropium in children and adults with CF. In the Phase II trial [16], both 2.5 and 5 mg of tiotropium resulted in significant lung function improvement compared with placebo, with a greater benefit of the 5 mg dose. Lung function was also improved in CF patients in a Phase III trial [17,19], although statistical significance was not reached; the pooled Phase II/III post hoc analysis showed a treatment difference in favor of tiotropium. Overall, tiotropium was well tolerated in patients with CF, with no treatment-related adverse events or unexpected safety findings, for a total exposure of 285 patient-years for the 5 mg dose. Tiotropium, as with other inhaled medications, is absorbed rapidly from the lower airways, reaching the maximum observed concentration within 5e7 min post treatment [7,8,20,21]. For inhaled medications, PK parameters relating to systemic availability and exposure are typically discussed in the context of safety, whereas they are not generally predictive of efficacy. The extensive PK data on tiotropium Respimat® in the management of COPD [20] (the approved indication) may be used to compare PK parameters of tiotropium in patients with CF. COPD is a useful comparator due to the large size of the COPD tiotropium PK dataset
and some similarities of the underlying obstructive component of the 2 diseases. The Respimat® SMI is suitable for patients of all ages, including children aged <5 years, when a valved holding chamber with facemask (spacer) is used [22,23]. This is of particular importance as CF is a genetic disease with lung involvement, in most cases beginning very early in life, and often requiring maintenance treatment with inhalation therapy including bronchodilators; hence, the suitability of the administration device plays an important role. The majority of CF patients are diagnosed through newborn screening, whereas COPD is more prevalent in people aged >40 years [24,25]. The current PK assessment of tiotropium in patients with CF therefore incorporates data from studies in patients with CF and comparative data from patients with COPD. The objectives of this pooled analysis of non-compartmental PK parameters across the CF clinical program [16e19] and including COPD studies [14,26], comprising a total of 9 trials, were: (1) to identify best estimates of standard PK parameters of tiotropium after a single dose and at steady state in patients with CF; (2) to describe the effect of a number of intrinsic and extrinsic factors; and (3) to compare the PK of tiotropium among healthy volunteers, patients with COPD, and patients with CF.
Table 1 Trial characteristics. Study and phase
Objectives of study
Study design and type of control
Test products and dosing regimen
N and type of subjects entered
Trial duration and PK sampling
205.112 [28] Phase I
Safety, tolerability, PK
14 days PK on Days 1, 7, and 14
Dose-ranging, PK
Total: 202 PK subset: 79 COPD patients
3 weeks Urine PK on Days 7, 14, and 21
205.249 [14] Phase III
Non-inferiority of tiotropium in Respimat® vs HandiHaler®, PK
Total: 131 PK subset: 63 COPD patients
28 weeks (treatment and washout periods 4 weeks) 12-h PK sampling at ss
205.250 [14] Phase III
Non-inferiority of tiotropium in Respimat® vs HandiHaler®, PK, efficacy and safety
Total: 76 PK subset: 35 COPD patients
28 weeks (treatment and washout periods 4 weeks) 12-h PK sampling at ss
205.338 [18] Phase I
Safety, tolerability, PK of single and multiple doses in CF patients
10, 20, 40 mg tiotropium qd via Respimat® (BINEB) (doses recalculated as tiotropium cation 8/16/32 mg) vs placebo 1.25, 2.5, 5, 10, 20 mg tiotropium qd via Respimat® vs placebo vs tiotropium HandiHaler® 18 mg qd 5, 10 mg tiotropium qd via Respimat® vs placebo via Respimat® vs tiotropium HandiHaler® 18 mg qd 5, 10 mg tiotropium qd via Respimat® vs placebo vs tiotropium HandiHaler® 18 mg qd 2.5, 5, 10 mg tiotropium qd via Respimat® vs placebo qd
36 healthy subjects
205.127 [26] Phase IIa
Randomized, placebocontrolled, multiple-dose, parallel-group study, double blind within groups Randomized, multiple-dose, placebo-controlled, intraform, double-blind, parallel-group, multicenter study Randomized, multiple-dose, double-blind, double-dummy, multicenter, placebocontrolled, 4-way crossover trial Randomized, multiple-dose, double-blind, double-dummy, multicenter, placebocontrolled, 4-way crossover trial Randomized, double-blind within dose, placebocontrolled, single- and multiple-dose, multicenter trial
28 days dosing 6-h PK sampling after single dose and/or at ssa
205.339 [16] Phase II
Safety, efficacy, PK in CF patients
2.5, 5 mg tiotropium qd via Respimat® vs placebo qd
205.438 [17,19] Phase III
Efficacy, long-term safety, PK in CF patients
Randomized, multiple-dose, double-blind, placebocontrolled, parallel-group, multicenter trial Randomized, multiple-dose, double-blind, placebocontrolled, parallel-group trial
Total: 112 PK subset: Single dose: 38 Multiple dose: 44 CF patients (5e11 and 12 yrs) Total: 510 PK subset: 484 CF patients (5e11 and 12 yrs) Total: 464 PK subset: 15 CF patients (<5 yrs)
1205.4 [29] Phase IIb
Dose finding of BEA2180 BR; Safety and efficacy of optimal BEA2180 BR dose compared with placebo and tiotropium Efficacy, safety of BEA2180 BR compared with placebo and tiotropium
1205.6 [27] Phase IIb
Randomized, multiple-dose, double-blind, placebo- and active-controlled, parallelgroup, multicenter trial Randomized, multiple-dose, double-blind, 4-way crossover, placebo- and active-controlled, multicenter trial
5 mg tiotropium qd via Respimat® vs placebo qd 5 mg tiotropium qd via Respimat® BEA 2180 BR 10, 20, 50, 100, 200 mg qd via Respimat® vs placebo qd 5 mg tiotropium qd via Respimat® BEA 2180 BR 200, 400 mg qd via Respimat® vs placebo qd
Total: 389 PK subset: 53 COPD patients
Total: 100 PK subset: 71 COPD patients
12 weeks 4-h PK sampling at ss
12 weeks 4-h urine sampling after single dose and at ss, predose urine sample at ss 4 weeks 6-h PK on Days 1, 8, 15, and 29
4 weeks 6-h PK on Days 1 and 29
Abbreviations: BINEB, Boehringer Ingelheim Nebulizer (former name of Respimat® device); BR, bromide; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; PK, pharmacokinetics; qd, once daily; ss, steady state. a The protocol was amended for the steady state, 5 mg dose in the 5e11 years age group, which was reduced to a single blood sample at 5 min post dosing.
The derivation of the following PK parameters was performed in the same way throughout the analysis. The area under the plasma concentrationetime curve (AUC) from time 1 to time 2 post dose after single dose, steady state (ss) or
431 286 32.0 60.0 165 (100.0) (0.0) (21e43) (62.0e100.0) (169e193) e e e e e e e e e e 27 0 30.0 78.0 180 (66.5) (33.5) (40e87) (42.6e141.0) (147e196) e e e e e e e e e e (46.7) (53.3) (18e69) (40.0e105.0) (147e191) (16.0e35.0) (1.3e2.3) (38.0e171.7) (25e130) (42.9) (50.0) (41.5) (6.6) (59.4) (70.3) 99 113 27.1 58.6 167 21.9 1.7 99.5 62 91 106 88 14 126 149 (70.0) (30.0) (12e17) (29.0e80.0) (141e192) (14.0e30.0) (1.1e2.1) (84.9e212.5) (27e132) (28.3) (43.3) (31.7) (1.7) (78.3) (85.0) 42 18 14.9 51.0 161 19.6 1.5 143.9 88 17 26 19 1 47 51 (56.6) (43.4) (5e11) (16.0e67.4) (111e163) (7.9e25.4) (0.7e1.7) (63.8e270.1) (51e125) (12.3) (26.2) (15.6) (2.5) (76.2) (81.1) 69 53 9.5 28.3 135 16.4 1.1 136.4 95 15 32 19 3 93 99 (46.7) (53.3) (0.4e4) (8.0e19.0) (66e106) (13.0e18.6) (0.4e0.7) (111.0e205.3) e e 3 (20.0) e e 5 (33.3) 10 (66.7)
219 Data presented as median (range) or N (%). Abbreviations: BMI, body mass index; BSA, body surface area; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; LABA, long-acting b2-agonist; N, number; OCS, oral corticosteroids. a Estimated using the Schwartz equation for patients aged <18 years (mL/min/1.73 m2) and the CockrofteGault equation for patients aged 18 years (mL/min).
2.4. Parameter derivation
Table 2 Population characteristics.
Sampling for quantification of drug plasma and urine concentrations is described for each trial in Table 1. Tiotropium concentrations were determined by validated assays using high-performance liquid chromatography coupled to tandem mass spectrometry and analyzed by Nuvisan Pharma Services GmbH & Co. KG, Neu-Ulm, Germany. The lower limit of quantification was 2.5 pg/mL.
<5 years n ¼ 15
2.3. Plasma and urine sampling
7 8 3.3 14.5 97 16.0 0.6 157.5
5e11 years n ¼ 122
This pooled analysis includes key PK parameters derived from plasma and urine samples using non-compartmental analysis based on the concentration data. The PK parameters excluded from the originally reported PK analyses of individual trials were also excluded for this pooled analysis, and time windows for assessing plasma concentrations were harmonized across trials, allowing ±1 min during the first 30 min post dosing and ±10 min for >30 min post dosing. The PK parameters were selected on the basis of their common availability across all the available trials. Only concentrations above the lower limits of detection were used for the calculation of these parameters (2.5 pg/mL).
Sex Male Female Age, years Body weight, kg Height, cm BMI, kg/m2 BSA, m2 Renal functiona Pre-dose FEV1, % predicted LABA use ICS use ICS and LABA use OCS use Dornase alfa use Mucolytics use (including dornase alfa)
2.2. PK parameters
12e17 years n ¼ 60
CF patients, N ¼ 409
18 years n ¼ 212
217 192 18.5 50.9 159 19.7 1.5 121.2 80 123 167 126 18 271 309
Total
COPD patients n ¼ 281
Healthy volunteers n ¼ 27
The tiotropium Respimat® data included in this pooled analysis originate from 9 clinical trials [14,16e19,26e29]. Ethical review for each trial was undertaken for each site/country by the local institutional review board/independent ethics committee and approval granted by the competent authority in each state. Written informed consent was obtained from each patient or their legal representative prior to randomization. All the PK parameters relating to tiotropium dose and age categories and the influence of intrinsic and extrinsic factors in patients with CF were derived from a clinical trial program consisting of 3 double-blind (Phase I blinded within dose group only), randomized, placebo-controlled multicenter trials of tiotropium Respimat® on top of standard of care in patients with CF [16e19]. Patients participating in the Phase I trial received a single dose (2.5, 5, or 10 mg) and/or multiple doses (2.5 or 5 mg) of tiotropium once daily, or placebo, for 28 days (Table 1). Patients in the Phase II trial received placebo, 2.5, or 5 mg (2 inhalations of 2.5 mg) once daily, for 12 weeks. Patients in the Phase III trial received 5 mg (2 inhalations of 2.5 mg) or placebo once daily, with an open-label extension (minimum 12 weeks and maximum 60 weeks). Inclusion criteria in the CF trials were broad (pre-bronchodilator forced expiratory volume in 1 s [FEV1] 25%, no upper limit for FEV1) to allow for inclusion of patients with all stages of lung disease. Tiotropium was administered as add-on to usual CF maintenance therapy in patients with CF of all ages. COPD PK data from 5 trials [14,26,27,29] were pooled to serve as a reference and to compare the exposure to tiotropium observed in patients with CF. A study assessing tiotropium in healthy volunteers was included for completeness [28]. Dosing and sampling regimens are described in Table 1, which provides an overview of the main characteristics of the trials included in the pooled analysis.
187 94 64.0 74.0 170
Total N ¼ 717
2.1. Trials and inclusion criteria
(53.1) (46.9) (0.4e69) (8.0e105.0) (66e192) (7.9e35.0) (0.4e2.3) (38.0e270.1) (25e132) (30.1) (40.8) (30.8) (4.4) (66.3) (75.6)
2. Methods
(60.1) (39.9) (0.4e87) (8.0e141.0) (66e196) e e e e e e e e e e
A. Sharma et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
220 Table 3 Overall summary descriptive statistics of key dose-normalized PK parameters of tiotropium following inhalation via Respimat® inhaler by dose and age category (dose range 2.5e10 mg) in patients with CF, and by indication (dose range: 8e32 mg for healthy volunteers, 2.5e10 mg for patients with CF and 5e20 mg for patients with COPD). C0.083,norm (pg/mL/mg) gMean (gCV %)
10 17
1.67 (50.1) 1.16 (68.2)
e 13 6 17
Indication CF 36 HV 19 COPD 75
Dose, mg 2.5 5 Age, years <5 5e11 12e17 18
N
Cpre,ss,norm (pg/mL/mg)
AUC0e1,norm (pg*h/mL/mg)
fe0e4 (%)
AUC0e1,ss,norm (pg*h/mL/mg)
fe0e6 (%)
fe0e4,ss (%)
fe0e6,ss (%)
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
68 82
2.48 (57.0) 2.02 (70.8)
e e
e e
e 6
e 0.97 (30.3)
7 10
2.03 (30.9) 1.37 (44.2)
20 39
1.82 (60.0) 1.04 (152)
19 27
2.38 (69.1) 2.09 (127)
152 178
4.70 (67.0) 4.04 (86.3)
18 22
9.52 (40.5) 6.21 (88.2)
e 0.88 (62.2) 1.15 (79.4) 1.64 (58.8)
e 39 16 95
e 1.87 (63.1) 1.79 (73.6) 2.47 (62.7)
e e e 9
e e e
e e e e
e e e e
e e e e
e e e e
13 25 8 22
0.40 1.41 3.12 1.94
e 26 9 21
e 1.70 (87.2) 3.78 (112) 2.73 (88.8)
14 96 48 172
1.19 4.09 4.03 5.07
e 18 6 16
e 6.20 (82.3) 8.05 (44.0) 9.12 (66.5)
1.23 (70.0) 0.66 (47.1) 2.07 (80.5)
150 e 80
2.22 (65.6) e 2.08 (72.2)
10 e 106
e e e
e e e
e e e
e e e
68 27 e
1.35 (124) 2.15 (94.1) e
56 e 104
2.31 (98.7) e 2.66 (95.1)
330 e e
4.33 (78.0) e e
40 e 111
7.52 (72.5) e 5.22 (121)
0.76 (30.5) 0.74 (30.7) e 0.53 (66.1)
(107) (70.3) (84.8) (89.1)
(52.9) (70.2) (65.1) (71.4)
N
gMean (gCV %)
Abbreviations: AUC, area under the curve; C, concentration; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; fe, fraction of drug excreted; gCV, geometric coefficient of variation; gMean, geometric mean; HV, healthy volunteer; N, number; norm, normalized; PK, pharmacokinetic; ss, steady state.
normalized by dose was derived using the linear trapezoid rule for areas between the 2 data points (t1, C1) and (t2, C2), if t2 > t1 and C2 C1 (AUCt1t2¼½(t2t1)(C1C2)) and the logarithmic trapezoid rule for the calculation of areas between the 2 data points (t1, C1) and (t2, C2), if t2 > t1 and C2 < C1 (AUCt1t2¼(t2t1)(C2C1)/ln[C2/C1]). The pre-dose steady-state plasma concentration of the analyte before administration of the next drug concentration, as well as the concentration of the analyte in plasma after single dose or following the last dose at steady state (5 min post dose: C0.083), were derived from the observed analyte plasma concentrationetime data allowing a time window of ±1 min from the planned time of sampling. Dose-normalized parameters were calculated by dividing by the tiotropium dose. The fraction of tiotropium dose excreted in urine (fe) during the time interval (h) after a single dose or following the last dose at steady state was derived with the following equation: fet1t2,ss¼Aet1t2,ss/Dose100.
2.5. Statistical analysis
The non-compartmental PK parameters were calculated using WinNonlin (Professional version 5.2 or higher, Pharsight
Fig. 1. Box plot of dose-normalized C0.083,ss,norm values (A), and fe0e4,ss values (B) of tiotropium following the administration of multiple doses of tiotropium, 2.5 and 5 mg, to steady state via Respimat® inhaler in patients with cystic fibrosis. Abbreviations: gMean, geometric mean; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
A. Sharma et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
N
C0.083,ss,norm (pg/mL/mg)
A. Sharma et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
Corporation, Mountain View, CA). Descriptive statistics, comparative tables, and listings were created using SAS® Version 9.2 (SAS Institute Inc., Cary, NC). Descriptive statistics were calculated when 3 observations were available within 1 category, and are given by age group, by dose, or by indication. N, geometric mean, geometric coefficient of variation, median, minimum, and maximum were calculated. Plasma concentration levels below the lower limit of quantification were not included in the estimation of descriptive statistics. Box plots were created when data from 6 patients were available; geometric mean was displayed as a line, and the 10th, 25th, 75th and 90th percentiles as boxes and whiskers. 3. Results 3.1. Population characteristics The characteristics of the population are shown in Table 2. There were 409 patients with CF, categorized within the age groups of <5, 5 to 11, 12 to 17, and 18 years, with a median age of 18.5 (range: 0.4e69) years. Pre-dose FEV1 and use of long-acting b2-agonists (LABAs), inhaled corticosteroids (ICS), oral corticosteroids (OCS), dornase alfa, and mucolytics (including dornase alfa) were comparable across the age categories, except for the youngest age group (<5 years), for whom FEV1 was not calculated and LABA, LABA þ ICS, and OCS were not prescribed. Total exposure of tiotropium in CF patients was 285 patient-years for the 5 mg dose.
221
Altogether 281 COPD patients, with a median age of 64 (range: 40e87) years, were used as a comparison disease group. The population of 27 healthy volunteers comprised only males and had a median age of 30 (range: 21e43) years. 3.2. PK parameters of patients with CF Various PK parameters were measured in patients with CF following once-daily inhalation of 2.5 or 5 mg of tiotropium Respimat®. The results are summarized by dose group (all trials pooled) in Table 3. The values of dose-normalized PK parameters C0.083,ss,norm and AUC0e1,ss,norm, as well as fe0e4,ss, were in a similar range for both tiotropium doses (Table 3 and Fig. 1), suggesting that these parameters follow a dose-proportional behavior in patients with CF. PK parameters obtained in patients with CF, summarized by age category (all trials pooled), are shown in Table 3. Patients with CF within all age groups aged 5 years had comparable C0.083,ss,norm and fe0e4,ss values. In contrast, the geometric mean fe0e4,ss values in patients with CF aged <5 years (fe0e4,ss: 1.19 [52.9]%) were 3.4-, 3.4-, and 4.3-fold lower than in patients aged 5 to 11, 12 to 17, and 18 years, respectively. Although the excreted fraction was lower in children aged <5 years than in those aged 5 years, their renal function, estimated based on glomerular filtration rate (GFR), was normal (estimated GFR range: 111.0e205.3 mL/min/1.73 m2) (Table 2).
Fig. 2. Box plots of dose-normalized C0.083,(ss),norm (A) and fe0e6,(ss) (B) values of tiotropium following the administration of a single dose (upper panels) and multiple doses (lower panels) of tiotropium via Respimat® inhaler with a comparison by indication (healthy volunteers [HV], and patients with CF and COPD; dose range: 8e32 mg for HV, 2.5e10 mg for patients with CF, and 5e20 mg for patients with COPD). Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; gMean, geometric mean; HV, healthy volunteers; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
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Further intrinsic and extrinsic factors evaluated (sex, height, body weight, body mass index, body surface area, renal function, pre-dose lung function, concomitant therapy with LABAs, inhaled antibiotics, ICS, ICS þ LABA, OCS, mucolytics (including dornase alfa), and dornase alfa) did not reveal an important influence on tiotropium PK parameters within the subgroups (data not shown). 3.3. PK parameter comparison by indication Tiotropium PK in patients with COPD was used as a reference for the PK parameters of patients with CF, and the comparison of the PK results by indication (CF vs COPD) is shown in Table 3. Following dosing to steady state, the dose-normalized geometric mean C0.083,ss,norm value was comparable between patients with CF and those with COPD. The dose-normalized geometric mean pre-dose concentration at steady state (Cpre,ss,norm) and the geometric mean fe0e6,ss value were 38% and 44% higher in patients with CF compared with those with COPD, respectively; however, there was considerable overlap between the 2 populations (Fig. 2). Geometric mean tiotropium plasma concentrationetime profile for patients with COPD and for patients with CF who were 5 to 11 or 12 years old were comparable at steady state (Fig. 3). PK parameters in healthy volunteers were only available after a single dose, and the C0.083,norm geometric mean (gCV%) in patients with CF and in those with COPD was higher than in healthy volunteers, although with
Fig. 3. Geometric mean tiotropium plasma concentration profile at steady state of 5 mg tiotropium via Respimat® inhaler in patients with CF aged 11 or 12 years and patients with COPD (A); and boxplot of fe0e4,ss values of tiotropium at steady state in patients with CF by age category (B). Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; gMean, geometric mean; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
considerable overlap between the 3 populations (Table 3 and Fig. 2). 4. Discussion There are currently no bronchodilators approved for the treatment of CF. Bronchodilators have, however, been shown to improve pulmonary function by relieving airway obstruction in individuals exhibiting bronchodilator responsiveness and bronchial hyperresponsiveness [6,30]. Tiotropium is the first bronchodilator to be studied in a comprehensive clinical program in patients with CF [16e19], which was part of an agreed pediatric investigational plan (PIP) approved by the European Medicines Agency (EMA) and other regulatory authorities as required by local laws and regulations. In this pooled analysis, the estimated standard PK parameters of tiotropium for patients with CF followed dose-proportional behavior. Systemic exposure increased with dose, as it did for patients with COPD [20]. For inhaled drugs, exposure is mainly a surrogate for safety; and in accord with the results from this pooled analysis, tiotropium was well tolerated, with relatively few treatment-related adverse events or unexpected safety findings observed in the Phase I, II, and III trials in patients with CF [16e19]. Since exposure in patients with CF and patients with COPD is similar, the extensive COPD safety dataset can be considered as supportive information to assess the safety of tiotropium Respimat® in patients with CF. The comparison of PK parameters by age group indicates that there was no difference in exposure to tiotropium in patients with CF aged 5 years (5 to 11, 12 to 17, and 18 years). However, the lower fraction of tiotropium dose excreted in urine and the lower variability of this parameter in children aged <5 years indicate a lower total exposure compared with older patients with CF, despite their estimated GFR being normal. Patients aged <5 years were using the Aerochamber Plus® (Trudell Medical International, London, Ontario, Canada) valved holding chamber with face mask (spacer) for inhalation with Respimat®, which reduces the delivered dose of most aerosols by ~40% [31] but may also reduce variability by eliminating the need to coordinate device actuation with inhalation. Further well-designed studies in this age group are justified to assess the potential age-specificity of tiotropium PK parameters in children <5 years. Since tiotropium exposure was lower in patients with CF aged <5 years than in those aged 5 years, it is unlikely that there may be additional dose-dependent safety issues in children aged <5 years over those observed in children 5 years. Despite the challenges of aerosol delivery in a very young age group, exposure was still achieved in children aged <5 years. For this age group, a lower dose may be adequate, taking into consideration their smaller lung and body sizes, since the difference in exposure was reduced when corrected for body weight. Across all age groups, tiotropium exposure was found to be independent of pre-dose lung function and co-administered drug use. The tiotropium PK parameters of C0.083,ss,norm and AUC0e1,ss,norm followed a dose-proportional behavior in patients with CF, although the values observed for the 2.5 mg dose were slightly higher than for the 5 mg dose, in particular for AUC0e1,ss,norm. This is because the proportion of plasma concentrations below the lower limit of quantification (2.5 pg/mL) (which were excluded) was higher in the lower dose group, and the results are therefore overestimated. Although trial inclusion criteria were broad and the number of patients participating in the CF trials was high when considering the small number of people affected by CF in the general population, absolute numbers were small. As both exposure and PK parameters were similar in CF and COPD patients, results from this analysis are reassuring in terms of safety in patients with CF.
A. Sharma et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
5. Conclusion This pooled analysis provided PK parameter estimates of tiotropium across CF trials and showed that these were similar to parameters derived from patients with COPD. The fraction of dose excreted in urine was, however, lower in patients with CF aged <5 years than in older patients. The evaluation of intrinsic and extrinsic factors tested did not reveal an important influence on the PK of tiotropium in patients with CF. Acknowledgments Writing assistance was provided by Sarah J. Petit of PAREXEL, funded by Boehringer Ingelheim. References [1] Ormerod LP, Thomson RA, Anderson CM, Stableforth DE. Reversible airway obstruction in cystic fibrosis. Thorax 1980;35(10):768e72. [2] Weinberger M. Airways reactivity in patients with CF. Clin Rev Allergy Immunol 2002;23(1):77e85. [3] Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996;154(5):1229e56. [4] Sawicki GS, Ren CL, Konstan MW, Millar SJ, Pasta DJ, Quittner AL. Treatment complexity in cystic fibrosis: trends over time and associations with sitespecific outcomes. J Cyst Fibros 2013;12(5):461e7. [5] Konstan MW, Vandevanter DR, Rasouliyan L, Pasta DJ, Yegin A, Morgan WJ, et al. Trends in the use of routine therapies in cystic fibrosis: 1995-2005. Pediatr Pulmonol 2010;45(12):1167e72. [6] Colombo JL. Long-acting bronchodilators in cystic fibrosis. Curr Opin Pulm Med 2003;9(6):504e8. [7] Spiriva HandiHaler Summary of Product Characteristics. emcþ website. Available from: http://www.medicines.org.uk/EMC/medicine/10039. [accessed on 14.1.14]. [8] Spiriva Respimat Summary of Product Characteristics. emcþ website. Available from: http://www.medicines.org.uk/EMC/medicine/20134/SPC/ SpirivaþRespimatþ2.5þmicrogramsþsolutionþforþinhalation/. [accessed on 14.1.14]. [9] Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D, et al. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis 2010;5:197e208. [10] Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, et al. A oneyear trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med 2010;104(10):1460e72. [11] Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, et al. Improvements in symptom-limited exercise performance over 8 h with oncedaily tiotropium in patients with COPD. Chest 2005;128(3):1168e78. [12] Niewoehner DE, Rice K, Cote C, Paulson D, Cooper Jr JA, Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143(5):317e26. [13] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359(15):1543e54. [14] van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med 2009;103(1):22e9.
223
[15] Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002;19(2):209e16. [16] Elborn JS, Sharma A, Deng Q, Koker P. A randomised, double-blind, placebocontrolled parallel group study to investigate the safety and efficacy of two doses of tiotropium bromide (2.5 mg and m5 g) administered once daily via the Respimat® device for 12 weeks in patients with cystic fibrosis [abstract] J Cyst Fibros 2011;10(Suppl. 1):S21. [17] Geller D, Koker P, Elborn S, Le Maulf F, Kattenbeck S, Moroni-Zentgraf P, et al. Tiotropium in cystic fibrosis: pooled analysis of phase II and III randomized, controlled trials [abstract] J Cyst Fibros 2013;12(Suppl. 1):S64. [18] Konstan M, Koker PJ, Sharma A. Evaluation of the safety, tolerability and pharmacokinetics of tiotropium bromide in cystic fibrosis patients [abstract] Pediatr Pulmonol Suppl 2008;31:367. [19] Ratjen F, Koker P, Geller D, Langellier-Cocteaux B, Le Maulf F, Kattenbeck S, et al. Tiotropium Respimat in cystic fibrosis: efficacy and safety results of phase III randomized placebo-controlled trial [abstract] J Cyst Fibros 2013;12(Suppl. 1):S64. [20] Hohlfeld J, Sharma A, van NJ, Cornelissen P, Derom E, Towse L, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. Online ahead of print 2013 Oct 25 [Epub ahead of print] J Clin Pharmacol 2013;54(4): 405e14. [21] Price D, Sharma A, Cerasoli F. Biochemical properties, pharmacokinetics and pharmacological response of tiotropium in chronic obstructive pulmonary disease patients. Expert Opin Drug Metab Toxicol 2009;5(4):417e24. [22] Kamin W, Bannemer-Schult K, Klemmer A, Schulze Schweinhorst P, Wachtel H, Zielen S. Flow profile data indicate that respimat with spacer is suitable for inhalation therapy of pre-school children. In: The 18th Congress of international society for aerosols in medicine; June 18-22; 2011 [Rotterdam, The Netherlands]. [23] Kamin W, Bannemer-Schult K, Klemmer A, Schulze Schweinhorst P, Wachtel H, Zielen S. Children below five years of age can handle Respimat® Soft Mist™ inhaler [abstract]. Am J Respir Crit Care Med 2010;181: A6254. [24] Steinraths M, Vallance HD, Davidson AG. Delays in diagnosing cystic fibrosis: can we find ways to diagnose it earlier? Can Fam Physician 2008;54(6): 877e83. [25] Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for chronic obstructive lung disease (GOLD) 2013. GOLD website. Available from: http://www.goldcopd.org/. [accessed on 29.7.13]. [26] Caillaud D, Le MC, Martinat Y, Aguilaniu B, Pavia D. A dose-ranging study of tiotropium delivered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis 2007;2(4):559e65. [27] Trial 1205.6: High dose trial in COPD. Clinicaltrials.gov website. Available from: http://clinicaltrials.gov/ct2/show/study/NCT00128440?term¼1205. 6&rank¼1. [accessed on 31.1.14]. [28] Feifel U, Wallenstein G, Rominger KL, Trommeshauser D, Platz J. Pharmacokinetics and tolerability (study 1) with particular reference to ocular safety (study 2) of tiotropium respimat soft mist inhaler: findings from two doseranging studies in healthy men. Int J Chron Obstruct Pulmon Dis 2008;3(3): 397e403. [29] Littner MR, van Noord JA, Moroni-Zentgraf P, Sigmund R, Joseph E, Karpel J. Phase IIb dose-finding study BEA2180 via Respimat in patients with chronic obstructive pulmonary diease (COPD) [abstract]. Respirology 2012;17(Suppl. 2):44. [30] Halfhide C, Evans HJ, Couriel J. Inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev 2005;4:CD003428. [31] Schultz A, Le Souef TJ, Venter A, Zhang G, Devadason SG, le Souef PN. Aerosol inhalation from spacers and valved holding chambers requires few tidal breaths for children. Pediatrics 2010;126(6):e1493e8.
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Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Pooled analysis of tiotropium Respimat® pharmacokinetics in cystic fibrosis Ashish Sharma a, *, David E. Geller b, 1, Petra Moroni-Zentgraf c, Sabine Kattenbeck d, Marion Schmid a, Katja Boland a, Barbara Rapp a, Michael W. Konstan e, Felix Ratjen f, J. Stuart Elborn g, Paul Koker h a
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, Biberach 88400, Germany Florida State University College of Medicine, Orlando, FL, USA Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Str. 173, Ingelheim 55216, Germany d Boehringer Ingelheim GmbH, Ingelheim, Binger Str. 173, Ingelheim 55216, Germany e Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106, USA f Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto M5G 1X8, Ontario, Canada g Centre for Infection and Immunity, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK h Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06776, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 May 2014 Received in revised form 12 August 2014 Accepted 15 August 2014 Available online 24 August 2014
Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat® in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat® across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and 18 years had similar tiotropium plasma concentrations (geometric mean C0.083,ss,norm: 2.22 pg/mL/mg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe0e4,ss: 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Tiotropium Respimat® inhaler Pharmacokinetics Cystic fibrosis
1. Introduction Cystic fibrosis (CF) is associated with airway obstruction, in part due to airway reactivity [1,2]. Around 90% of CF deaths are attributed to respiratory failure secondary to the combined effects of airway obstruction, infection, and inflammation [3]. Current
* Corresponding author. Tel.: þ49 7351 54 94779; fax: þ49 7351 54 90170. E-mail addresses: [email protected] (A. Sharma), [email protected] (D.E. Geller), [email protected] (P. Moroni-Zentgraf), sabine.kattenbeck@boehringer-ingelheim. com (S. Kattenbeck), [email protected] (M. Schmid), [email protected] (K. Boland), [email protected] (B. Rapp), [email protected] (M.W. Konstan), felix. [email protected] (F. Ratjen), [email protected] (J.S. Elborn), paul.koker@ boehringer-ingelheim.com (P. Koker). 1 Florida State University College of Medicine at time of study. Currently employed by AbbVie Inc., North Chicago, IL, USA. http://dx.doi.org/10.1016/j.pupt.2014.08.004 1094-5539/© 2014 Elsevier Ltd. All rights reserved.
treatment regimens are complex and burdensome for patients with CF [4]. More than 80% of patients with CF are prescribed short- or long-acting bronchodilators [5], mostly b2-adrenergic agonists, although none of these agents are approved by regulatory agencies for use in CF, and their therapeutic benefit has not been clearly defined [6]. Tiotropium is a long-acting anticholinergic bronchodilator administered by inhalation and approved for maintenance treatment in patients with chronic obstructive pulmonary disease (COPD) [7,8]. Tiotropium, delivered either by the multidose Respimat® Soft Mist Inhaler™ (SMI) (Boehringer Ingelheim, Ingelheim, Germany) or the HandiHaler® (Boehringer Ingelheim, Ingelheim, Germany), can provide 24-h sustained improvement in lung function and reduce hyperinflation, incidence of dyspnea, and the risk of exacerbations, resulting in an improved health-related quality of life [7e15]. Tiotropium has recently been systematically studied in a clinical program consisting of 3 placebo-controlled, multicenter trials of
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A. Sharma et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 217e223
tiotropium Respimat® [16e19] that investigated the safety, efficacy, and tolerability of inhaling single and multiple doses of tiotropium in children and adults with CF. In the Phase II trial [16], both 2.5 and 5 mg of tiotropium resulted in significant lung function improvement compared with placebo, with a greater benefit of the 5 mg dose. Lung function was also improved in CF patients in a Phase III trial [17,19], although statistical significance was not reached; the pooled Phase II/III post hoc analysis showed a treatment difference in favor of tiotropium. Overall, tiotropium was well tolerated in patients with CF, with no treatment-related adverse events or unexpected safety findings, for a total exposure of 285 patient-years for the 5 mg dose. Tiotropium, as with other inhaled medications, is absorbed rapidly from the lower airways, reaching the maximum observed concentration within 5e7 min post treatment [7,8,20,21]. For inhaled medications, PK parameters relating to systemic availability and exposure are typically discussed in the context of safety, whereas they are not generally predictive of efficacy. The extensive PK data on tiotropium Respimat® in the management of COPD [20] (the approved indication) may be used to compare PK parameters of tiotropium in patients with CF. COPD is a useful comparator due to the large size of the COPD tiotropium PK dataset
and some similarities of the underlying obstructive component of the 2 diseases. The Respimat® SMI is suitable for patients of all ages, including children aged <5 years, when a valved holding chamber with facemask (spacer) is used [22,23]. This is of particular importance as CF is a genetic disease with lung involvement, in most cases beginning very early in life, and often requiring maintenance treatment with inhalation therapy including bronchodilators; hence, the suitability of the administration device plays an important role. The majority of CF patients are diagnosed through newborn screening, whereas COPD is more prevalent in people aged >40 years [24,25]. The current PK assessment of tiotropium in patients with CF therefore incorporates data from studies in patients with CF and comparative data from patients with COPD. The objectives of this pooled analysis of non-compartmental PK parameters across the CF clinical program [16e19] and including COPD studies [14,26], comprising a total of 9 trials, were: (1) to identify best estimates of standard PK parameters of tiotropium after a single dose and at steady state in patients with CF; (2) to describe the effect of a number of intrinsic and extrinsic factors; and (3) to compare the PK of tiotropium among healthy volunteers, patients with COPD, and patients with CF.
Table 1 Trial characteristics. Study and phase
Objectives of study
Study design and type of control
Test products and dosing regimen
N and type of subjects entered
Trial duration and PK sampling
205.112 [28] Phase I
Safety, tolerability, PK
14 days PK on Days 1, 7, and 14
Dose-ranging, PK
Total: 202 PK subset: 79 COPD patients
3 weeks Urine PK on Days 7, 14, and 21
205.249 [14] Phase III
Non-inferiority of tiotropium in Respimat® vs HandiHaler®, PK
Total: 131 PK subset: 63 COPD patients
28 weeks (treatment and washout periods 4 weeks) 12-h PK sampling at ss
205.250 [14] Phase III
Non-inferiority of tiotropium in Respimat® vs HandiHaler®, PK, efficacy and safety
Total: 76 PK subset: 35 COPD patients
28 weeks (treatment and washout periods 4 weeks) 12-h PK sampling at ss
205.338 [18] Phase I
Safety, tolerability, PK of single and multiple doses in CF patients
10, 20, 40 mg tiotropium qd via Respimat® (BINEB) (doses recalculated as tiotropium cation 8/16/32 mg) vs placebo 1.25, 2.5, 5, 10, 20 mg tiotropium qd via Respimat® vs placebo vs tiotropium HandiHaler® 18 mg qd 5, 10 mg tiotropium qd via Respimat® vs placebo via Respimat® vs tiotropium HandiHaler® 18 mg qd 5, 10 mg tiotropium qd via Respimat® vs placebo vs tiotropium HandiHaler® 18 mg qd 2.5, 5, 10 mg tiotropium qd via Respimat® vs placebo qd
36 healthy subjects
205.127 [26] Phase IIa
Randomized, placebocontrolled, multiple-dose, parallel-group study, double blind within groups Randomized, multiple-dose, placebo-controlled, intraform, double-blind, parallel-group, multicenter study Randomized, multiple-dose, double-blind, double-dummy, multicenter, placebocontrolled, 4-way crossover trial Randomized, multiple-dose, double-blind, double-dummy, multicenter, placebocontrolled, 4-way crossover trial Randomized, double-blind within dose, placebocontrolled, single- and multiple-dose, multicenter trial
28 days dosing 6-h PK sampling after single dose and/or at ssa
205.339 [16] Phase II
Safety, efficacy, PK in CF patients
2.5, 5 mg tiotropium qd via Respimat® vs placebo qd
205.438 [17,19] Phase III
Efficacy, long-term safety, PK in CF patients
Randomized, multiple-dose, double-blind, placebocontrolled, parallel-group, multicenter trial Randomized, multiple-dose, double-blind, placebocontrolled, parallel-group trial
Total: 112 PK subset: Single dose: 38 Multiple dose: 44 CF patients (5e11 and 12 yrs) Total: 510 PK subset: 484 CF patients (5e11 and 12 yrs) Total: 464 PK subset: 15 CF patients (<5 yrs)
1205.4 [29] Phase IIb
Dose finding of BEA2180 BR; Safety and efficacy of optimal BEA2180 BR dose compared with placebo and tiotropium Efficacy, safety of BEA2180 BR compared with placebo and tiotropium
1205.6 [27] Phase IIb
Randomized, multiple-dose, double-blind, placebo- and active-controlled, parallelgroup, multicenter trial Randomized, multiple-dose, double-blind, 4-way crossover, placebo- and active-controlled, multicenter trial
5 mg tiotropium qd via Respimat® vs placebo qd 5 mg tiotropium qd via Respimat® BEA 2180 BR 10, 20, 50, 100, 200 mg qd via Respimat® vs placebo qd 5 mg tiotropium qd via Respimat® BEA 2180 BR 200, 400 mg qd via Respimat® vs placebo qd
Total: 389 PK subset: 53 COPD patients
Total: 100 PK subset: 71 COPD patients
12 weeks 4-h PK sampling at ss
12 weeks 4-h urine sampling after single dose and at ss, predose urine sample at ss 4 weeks 6-h PK on Days 1, 8, 15, and 29
4 weeks 6-h PK on Days 1 and 29
Abbreviations: BINEB, Boehringer Ingelheim Nebulizer (former name of Respimat® device); BR, bromide; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; PK, pharmacokinetics; qd, once daily; ss, steady state. a The protocol was amended for the steady state, 5 mg dose in the 5e11 years age group, which was reduced to a single blood sample at 5 min post dosing.
The derivation of the following PK parameters was performed in the same way throughout the analysis. The area under the plasma concentrationetime curve (AUC) from time 1 to time 2 post dose after single dose, steady state (ss) or
431 286 32.0 60.0 165 (100.0) (0.0) (21e43) (62.0e100.0) (169e193) e e e e e e e e e e 27 0 30.0 78.0 180 (66.5) (33.5) (40e87) (42.6e141.0) (147e196) e e e e e e e e e e (46.7) (53.3) (18e69) (40.0e105.0) (147e191) (16.0e35.0) (1.3e2.3) (38.0e171.7) (25e130) (42.9) (50.0) (41.5) (6.6) (59.4) (70.3) 99 113 27.1 58.6 167 21.9 1.7 99.5 62 91 106 88 14 126 149 (70.0) (30.0) (12e17) (29.0e80.0) (141e192) (14.0e30.0) (1.1e2.1) (84.9e212.5) (27e132) (28.3) (43.3) (31.7) (1.7) (78.3) (85.0) 42 18 14.9 51.0 161 19.6 1.5 143.9 88 17 26 19 1 47 51 (56.6) (43.4) (5e11) (16.0e67.4) (111e163) (7.9e25.4) (0.7e1.7) (63.8e270.1) (51e125) (12.3) (26.2) (15.6) (2.5) (76.2) (81.1) 69 53 9.5 28.3 135 16.4 1.1 136.4 95 15 32 19 3 93 99 (46.7) (53.3) (0.4e4) (8.0e19.0) (66e106) (13.0e18.6) (0.4e0.7) (111.0e205.3) e e 3 (20.0) e e 5 (33.3) 10 (66.7)
219 Data presented as median (range) or N (%). Abbreviations: BMI, body mass index; BSA, body surface area; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; LABA, long-acting b2-agonist; N, number; OCS, oral corticosteroids. a Estimated using the Schwartz equation for patients aged <18 years (mL/min/1.73 m2) and the CockrofteGault equation for patients aged 18 years (mL/min).
2.4. Parameter derivation
Table 2 Population characteristics.
Sampling for quantification of drug plasma and urine concentrations is described for each trial in Table 1. Tiotropium concentrations were determined by validated assays using high-performance liquid chromatography coupled to tandem mass spectrometry and analyzed by Nuvisan Pharma Services GmbH & Co. KG, Neu-Ulm, Germany. The lower limit of quantification was 2.5 pg/mL.
<5 years n ¼ 15
2.3. Plasma and urine sampling
7 8 3.3 14.5 97 16.0 0.6 157.5
5e11 years n ¼ 122
This pooled analysis includes key PK parameters derived from plasma and urine samples using non-compartmental analysis based on the concentration data. The PK parameters excluded from the originally reported PK analyses of individual trials were also excluded for this pooled analysis, and time windows for assessing plasma concentrations were harmonized across trials, allowing ±1 min during the first 30 min post dosing and ±10 min for >30 min post dosing. The PK parameters were selected on the basis of their common availability across all the available trials. Only concentrations above the lower limits of detection were used for the calculation of these parameters (2.5 pg/mL).
Sex Male Female Age, years Body weight, kg Height, cm BMI, kg/m2 BSA, m2 Renal functiona Pre-dose FEV1, % predicted LABA use ICS use ICS and LABA use OCS use Dornase alfa use Mucolytics use (including dornase alfa)
2.2. PK parameters
12e17 years n ¼ 60
CF patients, N ¼ 409
18 years n ¼ 212
217 192 18.5 50.9 159 19.7 1.5 121.2 80 123 167 126 18 271 309
Total
COPD patients n ¼ 281
Healthy volunteers n ¼ 27
The tiotropium Respimat® data included in this pooled analysis originate from 9 clinical trials [14,16e19,26e29]. Ethical review for each trial was undertaken for each site/country by the local institutional review board/independent ethics committee and approval granted by the competent authority in each state. Written informed consent was obtained from each patient or their legal representative prior to randomization. All the PK parameters relating to tiotropium dose and age categories and the influence of intrinsic and extrinsic factors in patients with CF were derived from a clinical trial program consisting of 3 double-blind (Phase I blinded within dose group only), randomized, placebo-controlled multicenter trials of tiotropium Respimat® on top of standard of care in patients with CF [16e19]. Patients participating in the Phase I trial received a single dose (2.5, 5, or 10 mg) and/or multiple doses (2.5 or 5 mg) of tiotropium once daily, or placebo, for 28 days (Table 1). Patients in the Phase II trial received placebo, 2.5, or 5 mg (2 inhalations of 2.5 mg) once daily, for 12 weeks. Patients in the Phase III trial received 5 mg (2 inhalations of 2.5 mg) or placebo once daily, with an open-label extension (minimum 12 weeks and maximum 60 weeks). Inclusion criteria in the CF trials were broad (pre-bronchodilator forced expiratory volume in 1 s [FEV1] 25%, no upper limit for FEV1) to allow for inclusion of patients with all stages of lung disease. Tiotropium was administered as add-on to usual CF maintenance therapy in patients with CF of all ages. COPD PK data from 5 trials [14,26,27,29] were pooled to serve as a reference and to compare the exposure to tiotropium observed in patients with CF. A study assessing tiotropium in healthy volunteers was included for completeness [28]. Dosing and sampling regimens are described in Table 1, which provides an overview of the main characteristics of the trials included in the pooled analysis.
187 94 64.0 74.0 170
Total N ¼ 717
2.1. Trials and inclusion criteria
(53.1) (46.9) (0.4e69) (8.0e105.0) (66e192) (7.9e35.0) (0.4e2.3) (38.0e270.1) (25e132) (30.1) (40.8) (30.8) (4.4) (66.3) (75.6)
2. Methods
(60.1) (39.9) (0.4e87) (8.0e141.0) (66e196) e e e e e e e e e e
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220 Table 3 Overall summary descriptive statistics of key dose-normalized PK parameters of tiotropium following inhalation via Respimat® inhaler by dose and age category (dose range 2.5e10 mg) in patients with CF, and by indication (dose range: 8e32 mg for healthy volunteers, 2.5e10 mg for patients with CF and 5e20 mg for patients with COPD). C0.083,norm (pg/mL/mg) gMean (gCV %)
10 17
1.67 (50.1) 1.16 (68.2)
e 13 6 17
Indication CF 36 HV 19 COPD 75
Dose, mg 2.5 5 Age, years <5 5e11 12e17 18
N
Cpre,ss,norm (pg/mL/mg)
AUC0e1,norm (pg*h/mL/mg)
fe0e4 (%)
AUC0e1,ss,norm (pg*h/mL/mg)
fe0e6 (%)
fe0e4,ss (%)
fe0e6,ss (%)
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
N
gMean (gCV %)
68 82
2.48 (57.0) 2.02 (70.8)
e e
e e
e 6
e 0.97 (30.3)
7 10
2.03 (30.9) 1.37 (44.2)
20 39
1.82 (60.0) 1.04 (152)
19 27
2.38 (69.1) 2.09 (127)
152 178
4.70 (67.0) 4.04 (86.3)
18 22
9.52 (40.5) 6.21 (88.2)
e 0.88 (62.2) 1.15 (79.4) 1.64 (58.8)
e 39 16 95
e 1.87 (63.1) 1.79 (73.6) 2.47 (62.7)
e e e 9
e e e
e e e e
e e e e
e e e e
e e e e
13 25 8 22
0.40 1.41 3.12 1.94
e 26 9 21
e 1.70 (87.2) 3.78 (112) 2.73 (88.8)
14 96 48 172
1.19 4.09 4.03 5.07
e 18 6 16
e 6.20 (82.3) 8.05 (44.0) 9.12 (66.5)
1.23 (70.0) 0.66 (47.1) 2.07 (80.5)
150 e 80
2.22 (65.6) e 2.08 (72.2)
10 e 106
e e e
e e e
e e e
e e e
68 27 e
1.35 (124) 2.15 (94.1) e
56 e 104
2.31 (98.7) e 2.66 (95.1)
330 e e
4.33 (78.0) e e
40 e 111
7.52 (72.5) e 5.22 (121)
0.76 (30.5) 0.74 (30.7) e 0.53 (66.1)
(107) (70.3) (84.8) (89.1)
(52.9) (70.2) (65.1) (71.4)
N
gMean (gCV %)
Abbreviations: AUC, area under the curve; C, concentration; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; fe, fraction of drug excreted; gCV, geometric coefficient of variation; gMean, geometric mean; HV, healthy volunteer; N, number; norm, normalized; PK, pharmacokinetic; ss, steady state.
normalized by dose was derived using the linear trapezoid rule for areas between the 2 data points (t1, C1) and (t2, C2), if t2 > t1 and C2 C1 (AUCt1t2¼½(t2t1)(C1C2)) and the logarithmic trapezoid rule for the calculation of areas between the 2 data points (t1, C1) and (t2, C2), if t2 > t1 and C2 < C1 (AUCt1t2¼(t2t1)(C2C1)/ln[C2/C1]). The pre-dose steady-state plasma concentration of the analyte before administration of the next drug concentration, as well as the concentration of the analyte in plasma after single dose or following the last dose at steady state (5 min post dose: C0.083), were derived from the observed analyte plasma concentrationetime data allowing a time window of ±1 min from the planned time of sampling. Dose-normalized parameters were calculated by dividing by the tiotropium dose. The fraction of tiotropium dose excreted in urine (fe) during the time interval (h) after a single dose or following the last dose at steady state was derived with the following equation: fet1t2,ss¼Aet1t2,ss/Dose100.
2.5. Statistical analysis
The non-compartmental PK parameters were calculated using WinNonlin (Professional version 5.2 or higher, Pharsight
Fig. 1. Box plot of dose-normalized C0.083,ss,norm values (A), and fe0e4,ss values (B) of tiotropium following the administration of multiple doses of tiotropium, 2.5 and 5 mg, to steady state via Respimat® inhaler in patients with cystic fibrosis. Abbreviations: gMean, geometric mean; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
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N
C0.083,ss,norm (pg/mL/mg)
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Corporation, Mountain View, CA). Descriptive statistics, comparative tables, and listings were created using SAS® Version 9.2 (SAS Institute Inc., Cary, NC). Descriptive statistics were calculated when 3 observations were available within 1 category, and are given by age group, by dose, or by indication. N, geometric mean, geometric coefficient of variation, median, minimum, and maximum were calculated. Plasma concentration levels below the lower limit of quantification were not included in the estimation of descriptive statistics. Box plots were created when data from 6 patients were available; geometric mean was displayed as a line, and the 10th, 25th, 75th and 90th percentiles as boxes and whiskers. 3. Results 3.1. Population characteristics The characteristics of the population are shown in Table 2. There were 409 patients with CF, categorized within the age groups of <5, 5 to 11, 12 to 17, and 18 years, with a median age of 18.5 (range: 0.4e69) years. Pre-dose FEV1 and use of long-acting b2-agonists (LABAs), inhaled corticosteroids (ICS), oral corticosteroids (OCS), dornase alfa, and mucolytics (including dornase alfa) were comparable across the age categories, except for the youngest age group (<5 years), for whom FEV1 was not calculated and LABA, LABA þ ICS, and OCS were not prescribed. Total exposure of tiotropium in CF patients was 285 patient-years for the 5 mg dose.
221
Altogether 281 COPD patients, with a median age of 64 (range: 40e87) years, were used as a comparison disease group. The population of 27 healthy volunteers comprised only males and had a median age of 30 (range: 21e43) years. 3.2. PK parameters of patients with CF Various PK parameters were measured in patients with CF following once-daily inhalation of 2.5 or 5 mg of tiotropium Respimat®. The results are summarized by dose group (all trials pooled) in Table 3. The values of dose-normalized PK parameters C0.083,ss,norm and AUC0e1,ss,norm, as well as fe0e4,ss, were in a similar range for both tiotropium doses (Table 3 and Fig. 1), suggesting that these parameters follow a dose-proportional behavior in patients with CF. PK parameters obtained in patients with CF, summarized by age category (all trials pooled), are shown in Table 3. Patients with CF within all age groups aged 5 years had comparable C0.083,ss,norm and fe0e4,ss values. In contrast, the geometric mean fe0e4,ss values in patients with CF aged <5 years (fe0e4,ss: 1.19 [52.9]%) were 3.4-, 3.4-, and 4.3-fold lower than in patients aged 5 to 11, 12 to 17, and 18 years, respectively. Although the excreted fraction was lower in children aged <5 years than in those aged 5 years, their renal function, estimated based on glomerular filtration rate (GFR), was normal (estimated GFR range: 111.0e205.3 mL/min/1.73 m2) (Table 2).
Fig. 2. Box plots of dose-normalized C0.083,(ss),norm (A) and fe0e6,(ss) (B) values of tiotropium following the administration of a single dose (upper panels) and multiple doses (lower panels) of tiotropium via Respimat® inhaler with a comparison by indication (healthy volunteers [HV], and patients with CF and COPD; dose range: 8e32 mg for HV, 2.5e10 mg for patients with CF, and 5e20 mg for patients with COPD). Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; gMean, geometric mean; HV, healthy volunteers; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
222
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Further intrinsic and extrinsic factors evaluated (sex, height, body weight, body mass index, body surface area, renal function, pre-dose lung function, concomitant therapy with LABAs, inhaled antibiotics, ICS, ICS þ LABA, OCS, mucolytics (including dornase alfa), and dornase alfa) did not reveal an important influence on tiotropium PK parameters within the subgroups (data not shown). 3.3. PK parameter comparison by indication Tiotropium PK in patients with COPD was used as a reference for the PK parameters of patients with CF, and the comparison of the PK results by indication (CF vs COPD) is shown in Table 3. Following dosing to steady state, the dose-normalized geometric mean C0.083,ss,norm value was comparable between patients with CF and those with COPD. The dose-normalized geometric mean pre-dose concentration at steady state (Cpre,ss,norm) and the geometric mean fe0e6,ss value were 38% and 44% higher in patients with CF compared with those with COPD, respectively; however, there was considerable overlap between the 2 populations (Fig. 2). Geometric mean tiotropium plasma concentrationetime profile for patients with COPD and for patients with CF who were 5 to 11 or 12 years old were comparable at steady state (Fig. 3). PK parameters in healthy volunteers were only available after a single dose, and the C0.083,norm geometric mean (gCV%) in patients with CF and in those with COPD was higher than in healthy volunteers, although with
Fig. 3. Geometric mean tiotropium plasma concentration profile at steady state of 5 mg tiotropium via Respimat® inhaler in patients with CF aged 11 or 12 years and patients with COPD (A); and boxplot of fe0e4,ss values of tiotropium at steady state in patients with CF by age category (B). Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; gMean, geometric mean; P10, 10th percentile; P90, 90th percentile; Q1, 1st quartile; Q3, 3rd quartile.
considerable overlap between the 3 populations (Table 3 and Fig. 2). 4. Discussion There are currently no bronchodilators approved for the treatment of CF. Bronchodilators have, however, been shown to improve pulmonary function by relieving airway obstruction in individuals exhibiting bronchodilator responsiveness and bronchial hyperresponsiveness [6,30]. Tiotropium is the first bronchodilator to be studied in a comprehensive clinical program in patients with CF [16e19], which was part of an agreed pediatric investigational plan (PIP) approved by the European Medicines Agency (EMA) and other regulatory authorities as required by local laws and regulations. In this pooled analysis, the estimated standard PK parameters of tiotropium for patients with CF followed dose-proportional behavior. Systemic exposure increased with dose, as it did for patients with COPD [20]. For inhaled drugs, exposure is mainly a surrogate for safety; and in accord with the results from this pooled analysis, tiotropium was well tolerated, with relatively few treatment-related adverse events or unexpected safety findings observed in the Phase I, II, and III trials in patients with CF [16e19]. Since exposure in patients with CF and patients with COPD is similar, the extensive COPD safety dataset can be considered as supportive information to assess the safety of tiotropium Respimat® in patients with CF. The comparison of PK parameters by age group indicates that there was no difference in exposure to tiotropium in patients with CF aged 5 years (5 to 11, 12 to 17, and 18 years). However, the lower fraction of tiotropium dose excreted in urine and the lower variability of this parameter in children aged <5 years indicate a lower total exposure compared with older patients with CF, despite their estimated GFR being normal. Patients aged <5 years were using the Aerochamber Plus® (Trudell Medical International, London, Ontario, Canada) valved holding chamber with face mask (spacer) for inhalation with Respimat®, which reduces the delivered dose of most aerosols by ~40% [31] but may also reduce variability by eliminating the need to coordinate device actuation with inhalation. Further well-designed studies in this age group are justified to assess the potential age-specificity of tiotropium PK parameters in children <5 years. Since tiotropium exposure was lower in patients with CF aged <5 years than in those aged 5 years, it is unlikely that there may be additional dose-dependent safety issues in children aged <5 years over those observed in children 5 years. Despite the challenges of aerosol delivery in a very young age group, exposure was still achieved in children aged <5 years. For this age group, a lower dose may be adequate, taking into consideration their smaller lung and body sizes, since the difference in exposure was reduced when corrected for body weight. Across all age groups, tiotropium exposure was found to be independent of pre-dose lung function and co-administered drug use. The tiotropium PK parameters of C0.083,ss,norm and AUC0e1,ss,norm followed a dose-proportional behavior in patients with CF, although the values observed for the 2.5 mg dose were slightly higher than for the 5 mg dose, in particular for AUC0e1,ss,norm. This is because the proportion of plasma concentrations below the lower limit of quantification (2.5 pg/mL) (which were excluded) was higher in the lower dose group, and the results are therefore overestimated. Although trial inclusion criteria were broad and the number of patients participating in the CF trials was high when considering the small number of people affected by CF in the general population, absolute numbers were small. As both exposure and PK parameters were similar in CF and COPD patients, results from this analysis are reassuring in terms of safety in patients with CF.
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5. Conclusion This pooled analysis provided PK parameter estimates of tiotropium across CF trials and showed that these were similar to parameters derived from patients with COPD. The fraction of dose excreted in urine was, however, lower in patients with CF aged <5 years than in older patients. The evaluation of intrinsic and extrinsic factors tested did not reveal an important influence on the PK of tiotropium in patients with CF. Acknowledgments Writing assistance was provided by Sarah J. Petit of PAREXEL, funded by Boehringer Ingelheim. References [1] Ormerod LP, Thomson RA, Anderson CM, Stableforth DE. Reversible airway obstruction in cystic fibrosis. Thorax 1980;35(10):768e72. [2] Weinberger M. Airways reactivity in patients with CF. Clin Rev Allergy Immunol 2002;23(1):77e85. [3] Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996;154(5):1229e56. [4] Sawicki GS, Ren CL, Konstan MW, Millar SJ, Pasta DJ, Quittner AL. Treatment complexity in cystic fibrosis: trends over time and associations with sitespecific outcomes. J Cyst Fibros 2013;12(5):461e7. [5] Konstan MW, Vandevanter DR, Rasouliyan L, Pasta DJ, Yegin A, Morgan WJ, et al. Trends in the use of routine therapies in cystic fibrosis: 1995-2005. Pediatr Pulmonol 2010;45(12):1167e72. [6] Colombo JL. Long-acting bronchodilators in cystic fibrosis. Curr Opin Pulm Med 2003;9(6):504e8. [7] Spiriva HandiHaler Summary of Product Characteristics. emcþ website. Available from: http://www.medicines.org.uk/EMC/medicine/10039. [accessed on 14.1.14]. [8] Spiriva Respimat Summary of Product Characteristics. emcþ website. Available from: http://www.medicines.org.uk/EMC/medicine/20134/SPC/ SpirivaþRespimatþ2.5þmicrogramsþsolutionþforþinhalation/. [accessed on 14.1.14]. [9] Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D, et al. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis 2010;5:197e208. [10] Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, et al. A oneyear trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med 2010;104(10):1460e72. [11] Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, et al. Improvements in symptom-limited exercise performance over 8 h with oncedaily tiotropium in patients with COPD. Chest 2005;128(3):1168e78. [12] Niewoehner DE, Rice K, Cote C, Paulson D, Cooper Jr JA, Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143(5):317e26. [13] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359(15):1543e54. [14] van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med 2009;103(1):22e9.
223
[15] Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002;19(2):209e16. [16] Elborn JS, Sharma A, Deng Q, Koker P. A randomised, double-blind, placebocontrolled parallel group study to investigate the safety and efficacy of two doses of tiotropium bromide (2.5 mg and m5 g) administered once daily via the Respimat® device for 12 weeks in patients with cystic fibrosis [abstract] J Cyst Fibros 2011;10(Suppl. 1):S21. [17] Geller D, Koker P, Elborn S, Le Maulf F, Kattenbeck S, Moroni-Zentgraf P, et al. Tiotropium in cystic fibrosis: pooled analysis of phase II and III randomized, controlled trials [abstract] J Cyst Fibros 2013;12(Suppl. 1):S64. [18] Konstan M, Koker PJ, Sharma A. Evaluation of the safety, tolerability and pharmacokinetics of tiotropium bromide in cystic fibrosis patients [abstract] Pediatr Pulmonol Suppl 2008;31:367. [19] Ratjen F, Koker P, Geller D, Langellier-Cocteaux B, Le Maulf F, Kattenbeck S, et al. Tiotropium Respimat in cystic fibrosis: efficacy and safety results of phase III randomized placebo-controlled trial [abstract] J Cyst Fibros 2013;12(Suppl. 1):S64. [20] Hohlfeld J, Sharma A, van NJ, Cornelissen P, Derom E, Towse L, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. Online ahead of print 2013 Oct 25 [Epub ahead of print] J Clin Pharmacol 2013;54(4): 405e14. [21] Price D, Sharma A, Cerasoli F. Biochemical properties, pharmacokinetics and pharmacological response of tiotropium in chronic obstructive pulmonary disease patients. Expert Opin Drug Metab Toxicol 2009;5(4):417e24. [22] Kamin W, Bannemer-Schult K, Klemmer A, Schulze Schweinhorst P, Wachtel H, Zielen S. Flow profile data indicate that respimat with spacer is suitable for inhalation therapy of pre-school children. In: The 18th Congress of international society for aerosols in medicine; June 18-22; 2011 [Rotterdam, The Netherlands]. [23] Kamin W, Bannemer-Schult K, Klemmer A, Schulze Schweinhorst P, Wachtel H, Zielen S. Children below five years of age can handle Respimat® Soft Mist™ inhaler [abstract]. Am J Respir Crit Care Med 2010;181: A6254. [24] Steinraths M, Vallance HD, Davidson AG. Delays in diagnosing cystic fibrosis: can we find ways to diagnose it earlier? Can Fam Physician 2008;54(6): 877e83. [25] Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for chronic obstructive lung disease (GOLD) 2013. GOLD website. Available from: http://www.goldcopd.org/. [accessed on 29.7.13]. [26] Caillaud D, Le MC, Martinat Y, Aguilaniu B, Pavia D. A dose-ranging study of tiotropium delivered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis 2007;2(4):559e65. [27] Trial 1205.6: High dose trial in COPD. Clinicaltrials.gov website. Available from: http://clinicaltrials.gov/ct2/show/study/NCT00128440?term¼1205. 6&rank¼1. [accessed on 31.1.14]. [28] Feifel U, Wallenstein G, Rominger KL, Trommeshauser D, Platz J. Pharmacokinetics and tolerability (study 1) with particular reference to ocular safety (study 2) of tiotropium respimat soft mist inhaler: findings from two doseranging studies in healthy men. Int J Chron Obstruct Pulmon Dis 2008;3(3): 397e403. [29] Littner MR, van Noord JA, Moroni-Zentgraf P, Sigmund R, Joseph E, Karpel J. Phase IIb dose-finding study BEA2180 via Respimat in patients with chronic obstructive pulmonary diease (COPD) [abstract]. Respirology 2012;17(Suppl. 2):44. [30] Halfhide C, Evans HJ, Couriel J. Inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev 2005;4:CD003428. [31] Schultz A, Le Souef TJ, Venter A, Zhang G, Devadason SG, le Souef PN. Aerosol inhalation from spacers and valved holding chambers requires few tidal breaths for children. Pediatrics 2010;126(6):e1493e8.