Abstract
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.
Highlights
Asthma and chronic obstructive pulmonary disease (COPD) represent inflammatory airway diseases that cause significant health problems to patients and a substantial economic burden on societies.[1,2]During the last decades, inhaled corticosteroids (ICS) have been the first-line treatment for patients with persistent asthma irrespective of disease severity.[1,3,4] Based on treatment guidelines, patients with asthma not sufficiently well controlled with ICS alone should have a long-acting b2agonist (LABA) added.[1]
For the test product and the median fine particle doses (FPDs) reference product BE was predicted. 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 in vivo correlation (IVIVC) analyses, and therapeutic equivalence between the products can be concluded
We report here the results of four PK studies that evaluated whether equivalent pulmonary deposition and systemic exposure were demonstrable after inhalation of budesonide/formoterol via Easyhaler and Turbuhaler
Summary
Asthma and chronic obstructive pulmonary disease (COPD) represent inflammatory airway diseases that cause significant health problems to patients and a substantial economic burden on societies.[1,2]During the last decades, inhaled corticosteroids (ICS) have been the first-line treatment for patients with persistent asthma irrespective of disease severity.[1,3,4] Based on treatment guidelines, patients with asthma not sufficiently well controlled with ICS alone (plus a rapid-acting bronchodilator used as needed) should have a long-acting b2agonist (LABA) added.[1]. We report here the results of four PK studies that evaluated whether equivalent pulmonary deposition (lung dose after blocking of the gastro-intestinal, GI, uptake with charcoal) and systemic exposure (without charcoal blockage) were demonstrable after inhalation of budesonide/formoterol via Easyhaler and Turbuhaler. 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. 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. 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 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
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