The systemic exposure to inhaled beclometasone/formoterol pmdi with valved holding chamber is independent of age and body size

YPUPT1369_proof ■ 18 April 2014 ■ 1/8 Contents lists available at Pulmonary Pharmacology & Therapeutics The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size Mirco Govoni ,, Annalisa Piccinno Germano Lucci , Gianluigi Poli Daniela Acerbi , Roberta Baronio , Dave Singh Piotr Kuna Bo L.K. Chawes Hans Bisgaard a Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma 43122, Italy b Department of Statistics and Data Management, Chiesi Farmaceutici, Parma 43122, Italy c University of Manchester, The Medicines Evaluation Unit, Manchester M23 9QZ, United Kingdom d Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, 90-153, Poland Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen & Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark Background: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage Received 28 January 2014 in children compared to older patients in order to minimize the systemic exposure and risk of unwanted Received in revised form side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actua- Accepted 5 April 2014 tion. However, the in fluence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of beclometasone-dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults.
Methods: The pharmacokinetics of formoterol and beclometasone-17-monopropionate (active metabo- lite of beclometasone-dipropionate) were evaluated over 8 h from three studies, each performed in a different age and body size group. Children (7e11 years, n ¼ 20), adolescents (12e17 years, n ¼ 29) and adults ("18 years, n ¼ 24) received a single dose of beclometasone/formoterol (children: 200 mg/24 mg, adolescents and adults: 400 mg/24 mg) via pMDI with AeroChamber Plus!.
Results: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for beclometasone-17-monopropionate in accordance with the halved dose of beclometasone administered in children (90% CIs within 0.8e1.25 for formoterol and 0.4e0.625 for beclometasone-17-monopropionate, respectively). The systemic exposure to beclometasone-17- monopropionate and formoterol was equivalent between adolescents and adults.
Conclusions: The systemic exposure to the active ingredients of a fixed dose combination of beclome- tasone/formoterol administered via pMDI with AeroChamber Plus! correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
" 2014 Published by Elsevier Ltd.
Abbreviations: AUC, area under the plasma drug concentration-time curve; BDP, International guidelines for treatment of childhood asthma such beclometasone-dipropionate; B17MP, beclometasone-17-monopropionate; Cmax, as GINA recommend prescription of inhaled corticosteroids maximum plasma concentration; FEV1, forced expiratory volume in 1 s; FF, for- moterol fumarate; ICS, inhaled corticosteroid; PK, pharmacokinetic; pMDI, pres- adjusted to age or body size The deposition of drug in the surized metered dose inhaler; t1/2, half-life; tmax, time to maximum plasma lungs determines the clinical response, whereas systemic exposure concentration; VHC, valved holding chamber.
in terms of drug concentration in the bloodstream determines the * Corresponding author. Department of Clinical Pharmacology, Chiesi Farm- risk of systemic side effects. Children in comparison to adolescents aceutici, Largo Francesco Belloli 11A, 43122 Parma, Italy. Tel.: þ39 0521 279 780; and adults under the same anti-asthmatics dose regimen may be þ39 0521 279 333.
E-mail addresses: , (M. Govoni).
exposed to significantly higher systemic concentrations due to their 1094-5539/" 2014 Published by Elsevier Ltd.
Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003 YPUPT1369_proof ■ 18 April 2014 ■ 2/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 lower body size. Thus the rationale behind age and body size dose <4.7 mm), the fine particle fraction (fine particle dose expressed as adjustment is to reduce the systemic exposure and minimize the % of the delivered dose), the coarse dose (induction port plus ACI risk of unwanted side effects in children. However, the influence of stages S0eS2; particles >4.7 mm), the mass median aerodynamic age and body size on the systemic exposure is not yet fully diameter (MMAD) and the geometric standard deviation (GSD) were also evaluated.
An extra-fine hydrofluoroalkane (HFA) fixed pressurized metered-dose inhaler (pMDI) combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) is licensed for use in asthmatic adults and currently under development in the pediat- Study data was collected from three independent clinical trials rics population. In children, pMDIs are recommended to be used in each performed on a different age group population, namely chil- combination with valved holding chambers (VHCs) to avoid the dren (7e11 years) [ClinicalTrials.gov ID: NCT01848769] ado- problem of coordinating inspiration with actuation. VHCs maxi- lescents (12e17 years) [ClinicalTrials.gov ID: and mize lung deposition and minimize the extra-thoracic delivery of adults ("18 years) [ClinicalTrials.gov ID: ]. Patients drug. In a recent scintigraphic study in which a FF pMDI with a documented clinical history of asthma diagnosed by the formulation with the same composition of BDP/FF pMDI , was responsible physician of each trial according to the GINA guidelines used in conjunction with AeroChamber Plus!, the extra-thoracic and under regular treatment with ICS or ICS/LABA or using drug delivery was minimized to less than 10% of the total nomi- short-acting inhaled b2-agonist as reliever to control asthma nal dose. Considering that only a fraction (oral systemic availability symptoms, were considered for inclusion in the study. Eligible ) of the extra-thoracic component contributes to the total patients were all those able to properly use a pMDI with VHC and blood levels, the systemic exposure of B17MP and formoterol after with a pre-bronchodilator forced expiratory volume in 1 s (FEV1) inhalation via BDP/FF pMDI with AeroChamber Plus! can be >70% ("60% for adults) of predicted values (% pred). Main exclusion considered a reasonable indicator of lung deposition.
criteria were exacerbation of asthma symptoms or lower respira- Debate remains regarding the safety of long-term use of inhaled tory tract infection within the previous 4 weeks and past or present corticosteroids/long acting b2-agonists (ICS/LABA) in children e diagnoses of cardiovascular, renal or liver disease.
Concerns primarily arose from short-term studies showing reduced lower leg growth rate and impact on the hypothalamic- pituitary-adrenal axis after using ICS . The clinical relevance of these findings is still unknown, but a recent large randomized Trials were conducted in accordance with the Declaration of controlled study of 943 children with asthma demonstrated a lower Helsinki (1996) and written informed consent was obtained from mean adult height of 1.2 cm in the budesonide treated children all patients.
compared to placebo Therefore, ICS in children have been The trial in children (EudraCT 2009-010434-22) was approved recommended at lower nominal doses of that recommended in by the Laegemiddelstyrelsen Danish Medicines Agency; approval number 2612-4085 on the 13 August 2009 and by the Region- In a previous study we found similar systemic exposure to a shuset, Viborg, The Health Secretariat, The Research Ethics Com- fixed nominal dose of budesonide delivered via a pMDI with VHC in mittees for the Region Midtjylland; Approval number 20090106.
children and adults This suggests that dose-reduction in The trial in adolescents (EudraCT 2011-005108-14) was relation to age may lead to significantly lower systemic exposures approved by the Office for Registration of Medicinal Products, in young patients, possibly reflecting a lower and sub-therapeutic Medical Devices and Biocidal Products 41 zabkowska str. 03-736 lung dose. In the present study, we have again investigated the Warsaw; approval: ur.dbl.ble.4500.430.2011 dated 30 Jan 2012 and influence of age and body size on the systemic exposure from an by the Bioethics Committee at the Medical University in Lodz 4 ICS/LABA fixed combination inhaled via pMDI with VHC. We kosciuszki av., 90-419 Lodz approval: rnn/221/11/ke dated 13 studied the systemic exposures to formoterol and beclometasone- December 2011.
17-monopropionate (B17MP; active metabolite of BDP) after a The trial in adults (EudraCT 2010-024384-40) was approved by single dose administration of BDP/FF pMDI used with AeroChamber the NRES e Committee North West e Greater Manchester Central Plus!. In order to disentangle the effects of age and body size, we M1 3DZ e ManchestereUK Approval: 11/NW/0160 15 Apr 2011 and studied three different asthma populations: (1) children aged 7e11 by the MHRA Approval: 06607/0243/001-0001 28 Apr 2011.
years, (2) adolescents aged 12e17 years, and (3) adults aged "18 2.4. Study design 2. Materials and methods Each age group population was dosed with an hydro- fluoroalkane (HFA)-propelled extra-fine fixed combination of BDP/ 2.1. In vitro study data FF pMDI (Chiesi Farmaceutici, Parma, Italy) in combination with AeroChamber Plus! (Trudell Medical International, Ontario, Can- An Andersen Cascade Impactor (ACI) (Copley Instruments, ada) in one of the treatment periods. In the present study the Nottingham, UK) operated at 28.3 l/min was used to determine the pharmacokinetic (PK) profiles of formoterol and B17MP in adults, particle size distributions of the pMDI with VHC used in the study adolescents and children obtained after administration of 4 puffs of at two different dose strengths of BDP/FF (100/6 mg and 50/6 mg per BDP/FF pMDI with AeroChamber Plus! was studied. In adults and actuation). Devices were actuated directly into the induction port of adolescents each actuation contained 100/6 mg (BDP/FF), giving a the impactor and the amount of drug collected at each stage was total dose of 400/24 mg. In children the BDP/FF dose was 50/6 mg per determined using a high performance liquid chromatography with actuation, giving a total dose of 200/24 mg pMDIs were primed prior U.V. detector fully validated method. The delivered dose was the to administration and the AeroChamber Plus! were cleaned in amount of drug deposited in the induction port as well as in all accordance with the instructions leaflet. The use of short acting b2- stages of the impactor (S0-Filter). The total emitted dose was the agonists, LABA and BDP, had to be avoided for at least 4, 24 and 48 h, delivered dose plus the amount of drug recovered in the actuator respectively, prior to study drug administration. At the end of and spacer. The fine particle dose (ACI stages S3-Filter; particles inhalation treatment, adult patients were given orally 5 g of Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003 YPUPT1369_proof ■ 18 April 2014 ■ 3/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 activated charcoal suspended in 50 mL of water; 1, 2 and 4 h after model and equivalence was demonstrated if the 90% CI range was the treatment, patients were given another dose of charcoal. Pa- within the 0.8e1.25 acceptance region An ANCOVA model tients practiced the inhalations with placebo pMDIs with Aero- with body surface area (BSA) or weight as covariate was used to Chamber Plus! until the investigator judged the technique to be assess the effect of these covariates on the systemic exposure optimal and were instructed to hold their breath for at least 5 s among different age-group populations Correlation assessments following each inhalation and to wait about 30 s before the next were performed using Pearson's analysis test. Statistical compari- inhalation. Evaluable patients were all those receiving BDP/FF pMDI sons of demography data were performed by means of one-way with AeroChamber Plus! excluding subjects without any valid ANOVA followed by post-hoc Dunnett's test for multiple pharmacokinetic (PK) measurement over 8 h post-dose or with major protocol deviations significantly affecting the PK, e.g. incor- rect inhalation, change in patient condition (worsening of asthma, cold), failure in delivery of the device, use of non-permitted med- ications. Study patients were not excluded on the basis of statistical 3.1. In vitro results analysis or for PK reasons.
The in vitro deposition parameters of BDP and FF for the 2.5. Pharmacokinetic assessments different strengths of BDP/FF pMDI used in combination with AeroChamber Plus! are shown in The total emitted dose Patients attended the clinics in the morning of the administra- matched with the nominal dose of BDP and FF for both strengths.
tion day after having fasted overnight and remained fasted until 2 h According to the nominal doses, the delivered dose (total emitted post-dosing. At each administration period, the patients were not dose subtracted by the amount of drug recovered in the actuator allowed to lie down or sleep for 2 h after administration, except fine particle dose (particles of the delivered dose when undergoing clinical assessments. They remained seated as <4.7 mm) of BDP was halved for BDP/FF 50/6 pMDI in comparison to much as possible and avoided strenuous activities and remained BDP/FF 100/6 pMDI while both these parameters were similar be- under constant surveillance of the nursing staff. No alcohol or tween the different strengths for FF. With the use of the Aero- xanthine (tea, chocolate, cola, etc.) containing beverages or foods, Chamber Plus! the fine particle fractions (fine particle dose or grapefruits were taken from 48 h before each drug administra- expressed as % of the delivered dose) approached 100% of the tion until 24 h after administration. No food or drink, except water, delivered dose and, accordingly, the coarse doses (particles of the was allowed for 2 h after drug administration.
>4.7 mm) were virtually completely abolished.
Blood samples were collected pre-dose and at 0.5, 1, 2, 4, 6, 8 h post dose. Samples for B17MP and formoterol determination in plasma were collected into vacuum tubes containing EDTA and 3.2. Study population lithium heparin, respectively. All samples were immediately chilled (ice bath) and plasma preparation was done within 15 min after Patient disposition is depicted in and demography data are blood collection. The plasma was separated in a refrigerated presented in .
centrifuge at þ4 $C and at 2500 rpm for 15 min and transferred into prelabelled polypropylene tubes. For stabilizing formoterol, the polypropylene tubes were pre-filled with 50 mL of citric acid and 26 patients were randomized in the children trial. Three were centrifuged before use in order to ensure that the citric acid was at withdrawn before receiving any treatment and one child was the bottom of each tube. Samples for B17MP and formoterol anal- withdrawn after treatment due to difficulties with blood sampling.
ysis were stored below %20 $C and %65 $C, respectively, before Two out of the remaining 22 children had no quantifiable study shipment on cold dry ice to the laboratory (SGS Life Sciences Ser- drug levels leaving 20 children evaluable for this study. Among vices, Belgium). The pharmacokinetic assays were performed using these patients, 15 were males (75%) and 5 were females (25%) and validated liquid chromatography-mass spectrometry (LC-MS/MS) their median (range) age was 9.5 (7e12 years).
methods with lower limit of quantification of 2 pg/ml for for- moterol and 50 pg/ml for B17MP The following PK parameters were calculated from the indi- vidual plasma concentrations versus time profiles: maximum In vitro characterization of beclometasone dipropionate (BDP) and formoterol fumarate (FF) for the different strengths of BDP/FF pMDI used in combination with max), time to maximum concentration (tmax), area AeroChamber Plus!.
under the concentration-time curve from 0 to last measurable point over 8 h and extrapolated to infinity (AUC BDP/FF 50/6 pMDI with BDP/FF 100/6 pMDI with respectively), half-life (t AeroChamber Plus! AeroChamber Plus! 1/2) calculated as 0.693/lz, where lz is the first-order terminal rate constant.
Total emitted dose (mg) 2.6. Data analysis Delivered dose(mg) Fine particle dose(mg) PK study calculations were performed according to a non- Fine particle fraction(%) 95.3 (2.3) compartmental kinetic model using Phoenix! WinNonlin# version 6.2.1 (Pharsight Corporation, Cary, USA). Statistical analysis of PK data were performed with SAS/STAT software, Version 9.2 of Results are expressed as the mean (SD), n the SAS System for Windows (Cary, USA) and GraphPad Prism# a Total emitted dose subtracted by the amount of drug recovered in the actuator version 6.0 (GraphPad Software, La Jolla, USA). All PK variables were and valved holding chamber.
log transformed before analysis. Comparisons of PK variables be- b Particles of the delivered dose <4.7 mm.
tween the different age-group populations were analyzed with an Fine particle fraction expressed as % of the delivered dose.
Particles of the delivered dose >4.7 mm.
analysis of variance (ANOVA) model. The 90% confidence intervals ¼ Mass Median Aerodynamic Diameter.
(CIs) for the ratio of the geometric means were derived from the f GSD ¼ Geometric Standard Deviation.
Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003 YPUPT1369_proof ■ 18 April 2014 ■ 4/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 Assessed for eligibility (n=27) Assessed for eligibility (n=30) Assessed for eligibility (n=36) -Not mee ng inclusion criteria (n=9) - Mee ng exclusion criteria - Mee ng exclusion criteria (n=3) Randomized (n=26) Randomized (n=30) Randomized (n=24) Allocated to interven on: Allocated to interven on: Allocated to interven on: (BDP/FF 50/6 pMDI with AeroChamber Plus™) (n=26) (BDP/FF 100/6 pMDI with AeroChamber Plus™) (n=30) (BDP/FF 100/6 pMDI with AeroChamber Plus™) (n=24) Receive interven on: (n=23) Receive interven on: (n=30) Receive interven on: (n=24) Did not receive interven on: (n=3) Did not receive interven on: (n=0) Did not receive interven on: (n=0) Discon nued interven on: (n=1) Discon nued interven on: (n=1) Discon nued interven on: (n=0) Excluded from analysis: (n=2) Excluded from analysis: (n=1) Excluded from analysis: (n=0) Fig. 1. Patient disposition.
3.2.2. Adolescents the bioequivalence reference range of 0.8 e1.25 for formoterol 30 patients were randomized in the adolescent trial. One subject (0.96 with 90% CI of 0.83 e1.12 for AUC0et and 0.94 with 90% CI of was discontinued due to insuf ficient number of samples taken after 0.80e1.12 for AUC0einf) ).
inhalation. This resulted in 29 adolescents evaluable for the present The mean plasma concentration-time pro files of B17MP and study. Among these patients 14 were males (48%) and 15 were fe- formoterol in adolescents compared to adults were similar over the males (52%) and their median (range) age was 16.0 (12 8-h sampling period (). Accordingly, the overall systemic exposure to both B17MP and formoterol was equivalent in adoles- cents compared to adults. The PE and 90% CI of the geometric means 24 patients were randomized in the adult trial; all of them were ratio adolescents/adults for AUC 0et and AUC0einf were within the evaluable for this study. Among these patients, 15 were males (63%) bioequivalence reference range; the PE of AUC 0et was 1.07 (90% CI of and 9 females (37%). The adults ' median (range) age was 45.5 (22e 0.93e1.22) for B17MP and 0.93 (90% CI of 0.82e1.05) for formoterol, while the PE of AUC 0einf was 1.07 (90% CI of 0.94e1.21) for B17MP In the three age group populations the mean body surface area and 0.93 (90% CI of 0.81 e1.08) for formoterol ( (BSA), calculated according to the Mosteller formula and the The terminal half-lives (t 1/2) for both B17MP and formoterol mean weight increased signi ficantly from children to adolescents were similar among the three age group populations. Mean (SD) t1/2 and from adolescents to adults (p for children, adolescents and adults were 2.1 (1.0) h, 3.0 (0.7) h and 3.2 (1.0) h for B17MP and 4.3 (1.7) h, 4.6 (1.4) h and 4.7 (1.2) h for 3.3. Pharmacokinetics Upon normalization for the BDP/FF dose in the three age group The overall summary of pharmacokinetic parameters is repre- populations (normalization of the BDP component in children to sented in . Children in comparison to adolescents and adults mg), the total systemic exposure to B17MP and formoterol were treated with a halved dose of BDP but with the same dose of 0einf did not correlate with the BSA (r ¼ %0.2, FF. Accordingly, the mean plasma concentration-time pro p ¼ 0.08 for B17MP and r ¼ 0.01, p ¼ 0.96 for formoterol), age pediatric population in comparison to older patients were ¼ %0.10, p ¼ 0.38 for B17MP and r ¼ 0.08, p ¼ 0.49 for formoterol) approximately halved for B17MP but comparable for formoterol ¼ %0.19, p ¼ 0.10 for B17MP and r ¼ 0.03, p ¼ 0.79 for (According to the dose given in the different age formoterol) of patients ). BSA or weight inserted as covariate group populations, the point estimate (PE) of the geometric means in an ANCOVA model for the analysis of the total systemic exposure ratio children/adolescents for AUC 0et and AUC0einf was 0.49 (90% CI to formoterol (compound given at the same dose among the three e0.58) and 0.48 (90% CI of 0.41e0.57) for B17MP, and within age-group populations) were not found significant for the Adolescents (n ¼ 29) 14.9 (1.7; 12e17) 42.4 (11.3; 22e65) 141 (10; 123e168) 168 (12; 139e191) 173 (10; 150e192) 17.7 (2.1; 14.9e23.4) 21.8 (2.8; 18.5e30.1) 26.9 (2.8; 22.4e31.6) 1.17 (0.14; 0.98e1.49) 1.69 (0.21; 1.24e2.10) 1.96 (0.23; 1.51e2.41) 2.09 (0.46; 1.27e3.03) 3.22 (0.82; 1.79e4.79) 2.74 (0.62; 1.71e4.09) Results are presented as the mean (SD; range). BMI: Body Mass Index; BSA: Body Surface Area calculated according to the Mosteller formula; FEV 1: Pre-bronchodilator forced expiratory volume in 1 s; FEV 1 % pred: FEV1 % of predicted normal value.
Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003

YPUPT1369_proof ■ 18 April 2014 ■ 5/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 Fig. 2. Mean body surface area and mean body weight (95% confidence intervals) among the different age group populations (****p < 0.0001).
comparisons between children and adolescents or adults and ad- to age or body size when prescribing a pMDI with VHC may be olescents (p > 0.1).
unnecessary to minimize the risk of systemic side effects in chil- dren and may cause sub-therapeutic lung dose.
4.2. Interpretation 4.1. Main finding The pharmacokinetic properties of a drug assuming mono- The systemic exposure to the active metabolite of BDP (B17MP) compartmental distribution in the body after absorption to the and formoterol after pMDI administration with AeroChamber systemic circulation can be analyzed by the following pharmaco- Plus! was independent of age and body size. The same dose of FF kinetic equation : Volume of distribution of the drug in the body compartment ðVÞ ¼ Amount of drug absorbed into the body compartment=ðAUC ( lzÞ administered through the pMDI with VHC in children, adolescents and adults led to comparable systemic exposures in the three The equation relates the volume of distribution of the drug in populations. For BDP, children received half the dosage of adoles- the body after systemic absorption, with the total amount of drug cents and adults which led to a corresponding reduction in the absorbed systemically, the total systemic exposure (AUC) and the systemic levels of B17MP to half of that recorded in adolescents and elimination constant (lz) calculated as 0.693/t1/2 . Reasonably, adults. Since dose proportionality can be demonstrated between the volume of drug distribution in the body, for the same drug, is the different strengths of BDP/FF pMDI and the systemic exposure proportional to the body surface area of individual patients. In our to B17MP and formoterol it follows that dosing children with specific study the BSA increased significantly from children to ad- the same amount of BDP as adolescents and adults would lead to olescents and from adolescents to adults while the half-lives and comparable systemic exposures among the three populations. This the systemic exposures were similar. It follows that the amount of is in agreement with our previous study of age-dependent dosing drug that reaches the systemic circulation after administration of showing similar PK-profiles in young children and adults receiving BDP/FF pMDI with AeroChamber Plus! is proportional to the BSA the same nominal dose of budesonide pMDI via the Nebuchamber (and therefore lower for young patients) with the net effect of spacer device These two studies together argue against a dose maintaining the same systemic exposure among the different age regimen adjusted to age and suggest that dose-reduction in relation group populations.
Beclometasone 17-monopropionate (B17MP) and formoterol pharmacokinetic parameters in children, adolescents and adults.
AUC0einf (pg*h/mL) Children (N ¼ 20) Adolescents (N ¼ 29) 3003.47 (1016.02) Children (N ¼ 20) Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003 YPUPT1369_proof ■ 18 April 2014 ■ 6/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 Pharmacokinetic analysis of beclometasone 17-monopropionate (B17MP) and for- moterol after administration of BDP/FF pMDI with AeroChamber Plus! in children and adults versus adolescents.
PK variable B17MP Children/Adolescents AUC The point estimate is calculated as ratio of the geometric means for the different PK Fig. 3. B17MP average plasma concentrations (95% con fidence intervals) after four inhalation of BDP/FF pMDI with AeroChamber Plus! (BDP/FF dose per actuation of 50 mg/6 mg in children and 100 mg/6 mg in adolescents and adults) for a total single BDP dose of 200 mg in children and 400 mg in adolescents and adults.
systemic absorption from the gastrointestinal tract. However, we have shown here and elsewhere that the use of AeroChamber As discussed above when BDP/FF pMDI is used in combination Plus! virtually abolishes the coarse particle fraction higher than with the AeroChamber Plus!, the entire dose inhaled via the VHC 4.7 mm that is potentially suitable for ingestion and GI absorption comprises the "respirable" fraction (<4.7 mm) with a limited This "spacer effect" was also demonstrated in vivo in healthy amount of drug reaching the extra-thoracic compartment This volunteers Indeed, the use of charcoal block did not affect the indicates that the overall systemic exposure observed in the study systemic availability of budesonide (oral bioavailability similar to has a predominant pulmonary origin and thereby largely reflects formoterol w10e20% after pMDI administration with lung exposure. Based on this consideration, the lower amount of Nebuhaler# spacer device In addition, we recently demon- drug reaching the systemic circulation in young patients could be strated in a scintigraphic study that after pMDI administration with explained by a reduced amount of the inhaled drug reaching the AeroChamber Plus! the extra-thoracic delivery of drug accounts lungs Indeed, the possibility of a reduced amount of drug for less than 10% of the total nominal dose in contrast to more the delivered to the lung in young patients in comparison to older 50% when the spacer is not used . Based on a delivered dose of patients may be explained by the decreased upper airway geometry approximately 60% of the total nominal dose () the extra- , the lower inspiratory capacity and/or the shorter inhalation thoracic and thoracic drug delivery would account for 16.6% (10/ times of the pediatric population 60*100) and 83.4% (100-16.6) of the delivered dose, respectively.
Taken together, the present results suggest that the appropriate Considering a thoracic systemic availability flung ¼ 1 and an extra- dosage of drug to be administered via a pMDI with VHC in children thoracic systemic availability foral ¼ 0.4 and 0.15, for B17MP and cannot be simply extrapolated from data in older patients upon formoterol, respectively , the systemic exposure could be correction for the age or body size. Indeed, for a normalized dose of derived by Eq. as follow: BDP/FF, the total systemic exposure to B17MP and formoterol did not correlate with the age BSA or weight of the patients. In other AUC ¼ AUClung þAUCoral ¼ delivereddose*0:834*flung ðV*lzÞ words, children cannot be regarded as little adults for this specific study drug, which is presumably a general finding for drugs inhaled via pMDI in combination with a VHC.
groupingdelivereddose=ðV*lzÞ ¼ K : ¼ K*0:834*flung þ K*0:166*foral; It is a limitation that adults, differently from adolescents and children, took a concomitant dose of charcoal block to prevent the *0:834*flung ¼ AUClung : ¼ AUClung þ AUClung*0:199* foral flung ¼ AUClung 1 þ 0:199 foral flung AUC (B17MP) ¼ AUClung*1.08 and AUC (formoterol) ¼ AUClung*1.03, i.e. the oral contribution to the systemic exposure would account for less than 8% and 3% for B17MP and formoterol, respectively.
Correcting the individual systemic exposures in adults for these values, the 90% CIs for the AUC0-t ratio adolescents/adults still fall within the 0.8e1.25 bioequivalence region (corrected 90% ¼ 0.86e1.11 for B17MP and 0.80e1.02 for formoterol).
Fig. 4. Formoterol average plasma concentrations (95% confidence intervals) after four inhalation of BDP/FF pMDI with AeroChamber Plus! (BDP/FF dose per actuation of The results of the present study demonstrate that the exposure mg/6 mg in children and 100 mg/6 mg in adolescents and adults) for a total single FF dose of 24 mg in each age group population.
to B17MP and formoterol after BDP/FF pMDI with AeroChamber Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003 YPUPT1369_proof ■ 18 April 2014 ■ 7/8 M. Govoni et al. / Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8 r = -019, p = 0.10 pg*h/ml 8.0
pg*h/ml 8.0
pg*h/ml 8.0
Age (years)
Weigth (kg)
r = 0.03, p = 0.79 r = 0.01, p = 0.96 r = 0.08, p = 0.49 pg*h/ml 4.5
pg*h/ml 4.5
Age (years)
Weight (kg)
Fig. 5. Correlation between the total systemic exposure to B17MP and formoterol with the body surface area (BSA), age and weight of individual patients. Correlations were considered significant at p < 0.05 (Pearson's analysis test). In children the systemic exposure to B17MP was normalized to a BDP dose of 400 mg.
Plus! correlates with the dose independently of patient age and Global strategy for asthma management and prevention. Workshop Report, body size. Thus, dose reduction in relation to age when using a updated 2012. Available on: ; 2012.
[2] Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al.
pMDI with VHC may be unnecessary for reducing the systemic Global strategy for asthma management and prevention: GINA executive exposure in children with asthma and runs the risk that sub- summary. Eur Respir J 2008;31(1):143 therapeutic doses reach the lungs.
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[4] National Asthma Education and Prevention Programme. Expert Panel: guidelines for the diagnosis and management of asthma All authors contributed to study design conceptualization, [5] Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, analysis and interpretation, and manuscript preparation and/or et al. Definition, assessment and treatment of wheezing disorders in pre- critical revision.
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[7] Häussermann S, Acerbi D, Brand P, Herpich C, Poli G, Sommerer K, et al. Lung This study was financially supported by Chiesi Farmaceutici deposition of formoterol HFA (Atimos/Forair) in healthy volunteers, asthmatic S.p.A; Mirco Govoni, Annalisa Piccinno, Germano Lucci, Gianluigi and COPD patients. J Aerosol Med 2007;20(3):331e41.
Poli, Roberta Baronio and Daniela Acerbi are employed at Chiesi [8] Singh D, Collarini S, Poli G, Acerbi D, Amadasi A, Rusca A. Effect of Aero- Farmaceutici S.p.A that sponsored the clinical trials in children, Chamber Plus! on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI. Br J Clin Pharmacol 2011;72(6):932e9.
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Please cite this article in press as: Govoni M, et al., The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holdingchamber is independent of age and body size, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.003

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