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Differences in Relative Bioavailability (BA) of Inhalation Insulin Determined using Insulin and Glucose Levels Following Subcutaneous and Inhalation Administration in Humans

Chyung S. Cook, Paul W. Valaitis, Andrew Brugger, Tim Heise, Jerry Gass, Laura Anderson, Janice Troeger, Steve White, Uta Eckers, Leszek Nosek, Klause Rave and Lutz Heinemann

BA may be determined using both plasma concentrations of a drug (pharmacokinetic parameters) and its pharmacological effects (pharmacodynamic parameters). However, the resulting assessments of BA can be substantially different. In a relative BA study (N=30) 10 IU (0.35 mg) Actrapid ® was administered subcutaneously with comparison to a 6.5 mg dose of recombinant human insulin inhalation powder (RHIIP) administered using the Cyclohaler TM dry powder inhaler under euglycemic glucose clamp conditions. Relative BA following the inhalation administration compared with the subcutaneous dose was 12.0±1.8% and 6.3±0.6% when determined using baseline-adjusted insulin and glucose infusion rate (GIR), respectively. To explain the observed differences in BA, a pharmacokinetic-pharmacodynamic model was developed and BAs were predicted at different doses of inhalation insulin with the fixed 10 IU subcutaneous dose. BA predicted for 3.25 mg inhaled insulin and GIR were 12% and 7.5%, respectively. When the potency of the two insulin formulations was compared, it was shown that Actrapid ® was approximately 1.4 times greater than the RHIIP formulation. Furthermore, when AUC values for GIR were normalized based on potency BA predicted for a 3.25 mg RHIIP dose was approximately 11%. Thus, the difference in BA dependent upon insulin and glucose could be explained by the non-linear pharmacokinetic-pharmacodynamic relationship and potency difference between RHIIP and Actrapid ® .

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