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    The International Society for Aerosols in Medicine

    Dennis Sandell

    Dennis Sandell

    Dennis Sandell

    S5 Consulting  
    Blentarp, Sweden

    Dr. Sandell is a world leading expert in the area of CMC statistics, especially related to inhalation products. He has a special interest in in-vitro bioequivalence evaluations as well as correlating in-vitro data with results from pharmacokinetic studies. Dr. Sandell is an independent consultant, has 90+ publications and is a member of USP Statistics Expert Committee

     

    Pharmacokinetic comparison of a budesonide/formoterol DPI and Symbicort® Turbuhale® using a multi-batch approach

    Abstract
    Dennis Sandell1, Giovanni Caponetti2, Marina Fertek3, Luca Raiteri2, Anders Fuglsang4 and Charlotte Keywood2
    1S5 Consulting, Blentarp, Sweden; 2 Zambon SpA, Milan, Italy; 3Independent Consultant, Prague, Czech Republic; 4Fuglsang Pharma, Haderslev, Denmark

    A blend of spray dried budesonide (BUD) and formoterol fumarate dihydrate (FFD) produced using the Edry® particle engineering technology is mixed with micronized lactose to create a unique formulation to be delivered using a standard Plastiape RS-01 capsule inhaler. The product “Z7200” is intended as an alternative to the originator product, Symbicort Turbohaler (“SymbTBH”, AstraZeneca). Z7200 has a very high fine particle fraction of ~70%, and was developed to have the same efficacy with a 50% reduction of the delivered dose. Z7200 80/2.25 μg and SymbTBH 160/4.5 μg were compared in an open-label, randomized, five-period crossover study in 90 healthy volunteers to assess bioequivalence of a single dose (two inhalations), with and without charcoal. As SymbTBH might have high between batch variability, a multi-batch approach with 9 reference batches was used. The results showed FFD bioequivalence in both AUC0-t and Cmax, both with and without charcoal block. For BUD, bioequivalence was found for AUC0-t but Cmax failed. As several reference batches were studied in the PK study, it was of interest to assess how different PK parameters correlate to in-vitro data for the same batches. No correlation between BUD AUC0-tand fine particle mass (FPM) was seen. The between batch RSD in FPM and AUC0-t was 16% and 11%, respectively. Thus, the results for SymbTBH suggest that this product has high between batch PK variability, and that FPM alone is no reliable predictor of in-vivo performance.