Effect of a spacer on total systemic and lung bioavailability in healthy volunteers and in vitro performance of the Symbicort® (budesonide/formoterol) pressurized metered dose inhaler.

INTRODUCTION: Many patients with chronic obstructive pulmonary disease or asthma experience difficulties in coordinating inhalation with pressurized metered-dose inhaler (pMDI) actuation. The use of a spacer device can improve drug delivery in these patients. The aim of this study was to establish the relative bioavailability of single doses of Symbicort® (budesonide/formoterol) pMDI 160/4.5 µg/actuation (2 actuations) used with and without a spacer device. In addition, an in vitro study was conducted to characterize performance of the inhaler when used in conjunction with a spacer device. METHODS: A Phase I, randomized, open-label, single-dose, single-center, crossover study in 50 healthy volunteers (NCT02934607) assessed the relative bioavailability of single-dose Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) with and without a spacer (AeroChamber Plus® Flow-Vu®). Inhaled doses were administered without or with activated charcoal (taken orally) to estimate total systemic exposure and exposure through the lung, respectively. The in vitro study characterized the effect of the spacer with respect to delivered dose, fine particle dose, and dose during simulated breathing of budesonide and formoterol. RESULTS: In terms of total systemic exposure, use of the spacer increased the relative bioavailability determined by AUC(0-last) and Cmax by 68% (spacer:no spacer treatment ratio, 167.9%; 90% CI, 144.1 to 195.6) and 99% (ratio, 198.7%; 90% CI, 164.4 to 240.2) for budesonide, and 77% (ratio, 176.6%; 90% CI, 145.1 to 215.0) and 124% (ratio, 223.6%; 90% CI, 189.9 to 263.3) for formoterol, respectively, compared with pMDI alone. Similarly, the lung exposure of budesonide and formoterol increased (AUC(0-last) and Cmax by 146% [ratio, 246.0%; 90% CI, 200.7 to 301.6] and 127% [ratio, 226.5%; 90% CI, 186.4 to 275.4] for budesonide, and 173% [ratio, 272.8%; 90% CI, 202.5 to 367.4] and 136% [ratio, 236.2%; 90% CI, 192.6 to 289.6] for formoterol, respectively) when the pMDI was administered through the spacer. When assessed by AUC(0-last) quartile without spacer, subjects in the lowest exposure quartile (indicating poor inhalation technique) with Symbicort® pMDI 160/4.5 µg/actuation (2 actuations) had markedly increased total systemic and lung exposure when the same dose was administered with the spacer. In contrast, for subjects in the highest exposure quartile with pMDI alone, total systemic and lung exposure of formoterol and budesonide was similar with and without the spacer. In the in vitro study, the fine particle dose (<5 µm) of both budesonide and formoterol from the spacer at delay time (i.e. pause period after actuation) = 0 s (instantaneous) after actuation was similar to the fine particle dose when not using the spacer. The delivered doses of budesonide and formoterol from the spacer were both lower compared with the doses administered without the spacer. There was also a decrease in delivered dose with increasing delay time. CONCLUSIONS: The clinical study demonstrated that in subjects with poor inhalation technique the use of the AeroChamber Plus® Flow-Vu® spacer increased the bioavailability of Symbicort® pMDI to a level observed in subjects with good inhalation technique without a spacer. The findings from the in vitro study support the fine particle dose characteristics of Symbicort® pMDI with the AeroChamber Plus® Flow-Vu® spacer.

Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD.

Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting ß2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 µg and FF MDI 9.6 µg, and two of either BFF MDI 160/9.6 µg, BFF MDI 80/9.6 µg, or BD MDI 320 µg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 µg (least squares mean differences 186-221 mL; all p<0.0001), and BFF MDI 320/9.6 µg demonstrated a significant improvement versus FF MDI 9.6 µg (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 µg for all lung function, dyspnea, and rescue medication use secondary efficacy endpoints. All BFF MDI doses were well tolerated, and the safety profile was not substantially different from the monocomponents. There was no evidence of clinically meaningful pharmacokinetic interactions when budesonide and formoterol were formulated together in BFF MDI. Conclusion: The findings presented here confirm that BFF MDI 320/9.6 µg is an appropriate dose to take forward into Phase III studies in patients with COPD.

On the pharmacokinetics of two inhaled budesonide/formoterol combinations in asthma patients using modeling approaches.

Dry powder inhalers containing the budesonide/formoterol combination have currently a well-established position among other inhaled products. Even though their efficacy mainly depends on the local concentrations of the drug they deliver within the lungs, their safety profile is directly related to their total systemic exposure. The aim of the present investigation was to explore the absorption and disposition kinetics of the budesonide/formoterol combination delivered via two different dry powder inhalers in asthma patients. Plasma concentration-time data were obtained from a single-dose, crossover bioequivalence study in asthma patients. Non-compartmental and population compartmental approaches were applied to the available datasets. The non-compartmental analysis allowed for an initial characterization of the primary pharmacokinetic (PK) parameters of the two inhaled drugs and subsequently the bioequivalence assessment of the two different dry powder inhalers. The population pharmacokinetic analysis further explored the complex absorption and disposition characteristics of the two drugs. In case of inhaled FOR, a five-compartment PK model including an enterohepatic re-circulation process was developed. For inhaled BUD, the incorporation of two parallel first-order absorption rate constants (fast and slow) for lung absorption in a two-compartment PK model emphasized the importance of pulmonary anatomical features and underlying physiological processes during model development. The role of potential covariates on the variability of the PK parameters was also investigated.

Numerical simulation of emitted particle characteristics and airway deposition distribution of Symbicort(®) Turbuhaler(®) dry powder fixed combination aerosol drug.

One of the most widespread dry powder fixed combinations used in asthma and chronic obstructive pulmonary disease (COPD) management is Symbicort(®) Turbuhaler(®). The aim of this study was to simulate the deposition distribution of both components of this drug within the airways based on realistic airflow measurements. Breathing parameters of 25 healthy adults (11 females and 14 males) were acquired while inhaling through Turbuhaler(®). Individual specific emitted doses and particle size distributions of Symbicort(®) Turbuhaler(®) were determined. A self-developed particle deposition model was adapted and validated to simulate the deposition of budesonide (inhaled corticosteroid; ICS) and formoterol (long acting ß2 agonist; LABA) in the upper airways and lungs of the healthy volunteers. Based on current simulations the emitted doses varied between 50.4% and 92.5% of the metered dose for the ICS, and between 38% and 96.1% in case of LABA component depending on the individual inhalation flow rate. This variability induced a notable inter-individual spread of the deposited lung doses (mean: 33.6%, range: 20.4%-48.8% for budesonide and mean: 29.8%, range: 16.4%-42.9% for formoterol). Significant inter-gender differences were also observed. Average lung dose of budesonide was 29.2% of the metered dose for females and 37% for males, while formoterol deposited with 26.4% efficiency for females and 32.5% for males. Present results also highlighted the importance of breath-holding after inhalation of the drug. About a half of the total lung deposition occurred during breath-hold at 9.6s average breath-hold time. Calculated depositions confirmed appropriate lung deposition of Symbicort(®) Turbuhaler(®) for both genders, however more effort for optimal inhalation technique is advised for persons with low vital capacity. This study demonstrated the possibility of personalized prediction of airway deposition of aerosol drugs by numerical simulations. The methodology developed in this study will be applicable also to other marketed drugs in the future.

Permeation of Therapeutic Drugs in Different Formulations across the Airway Epithelium In Vitro.

BACKGROUND: Pulmonary drug delivery is characterized by short onset times of the effects and an increased therapeutic ratio compared to oral drug delivery. This delivery route can be used for local as well as for systemic absorption applying drugs as single substance or as a fixed dose combination. Drugs can be delivered as nebulized aerosols or as dry powders. A screening system able to mimic delivery by the different devices might help to assess the drug effect in the different formulations and to identify potential interference between drugs in fixed dose combinations. The present study evaluates manual devices used in animal studies for their suitability for cellular studies. METHODS: Calu-3 cells were cultured submersed and in air-liquid interface culture and characterized regarding mucus production and transepithelial electrical resistance. The influence of pore size and material of the transwell membranes and of the duration of air-liquid interface culture was assessed. Compounds were applied in solution and as aerosols generated by MicroSprayer IA-1C Aerosolizer or by DP-4 Dry Powder Insufflator using fluorescein and rhodamine 123 as model compounds. Budesonide and formoterol, singly and in combination, served as examples for drugs relevant in pulmonary delivery. RESULTS AND CONCLUSIONS: Membrane material and duration of air-liquid interface culture had no marked effect on mucus production and tightness of the cell monolayer. Co-application of budesonide and formoterol, applied in solution or as aerosol, increased permeation of formoterol across cells in air-liquid interface culture. Problems with the DP-4 Dry Powder Insufflator included compound-specific delivery rates and influence on the tightness of the cell monolayer. These problems were not encountered with the MicroSprayer IA-1C Aerosolizer. The combination of Calu-3 cells and manual aerosol generation devices appears suitable to identify interactions of drugs in fixed drug combination products on permeation.

Equivalent Lung Dose and Systemic Exposure of Budesonide/Formoterol Combination via Easyhaler and Turbuhaler.

BACKGROUND: Easyhaler(®) device-metered dry powder inhaler containing budesonide and formoterol fumarate dihydrate (hereafter formoterol) for the treatment of asthma and chronic obstructive pulmonary disease has been developed. The current approvals of the product in Europe were based on several pharmacokinetic (PK) bioequivalence (BE) studies, and in vitro-in vivo correlation (IVIVC) modeling. METHODS: Four PK studies were performed to compare the lung deposition and total systemic exposure of budesonide and formoterol after administration of budesonide/formoterol Easyhaler and the reference product, Symbicort Turbuhaler. The products were administered concomitantly with oral charcoal (lung deposition) and in two of the studies also without charcoal (total systemic exposure). Demonstration of BE for lung deposition (surrogate marker for efficacy) and non-inferiority for systemic exposure (surrogate marker for safety) were considered a proof of therapeutic equivalence. In addition, IVIVC models were constructed to predict study outcomes with different reference product fine particle doses (FPDs). RESULTS: In the first pivotal study, the exposure and lung dose via Easyhaler were higher compared to the reference product (mean comparison estimates between 1.07 and 1.28) as the FPDs of the reference product batch were low. In the following studies, reference product batches with higher FPDs were utilized. In the second pivotal study, non-inferiority of Easyhaler compared to Turbuhaler was shown in safety and BE in efficacy for all other parameters except the formoterol AUCt. In the fourth study where two reference batches were compared to each other and Easyhaler, budesonide/formoterol Easyhaler was bioequivalent with one reference batch but not with the other having the highest FPDs amongst the 28 reference batches studied. In the IVIVC based study outcome predictions, the test product was bioequivalent with great proportion of the reference batches. For the test product and the median FPD reference product BE was predicted. CONCLUSIONS: Equivalence regarding both safety and efficacy between budesonide/formoterol Easyhaler and Symbicort Turbuhaler was shown based on totality of evidence from the PK studies and IVIVC analyses, and therefore, therapeutic equivalence between the products can be concluded. The results of the PK studies are likely dependent on the variability of FPDs of the reference product batches.