Efficient deposition and absorption of orally inhaled indacaterol in the lungs

Introduction: Indacaterol (IND) is an inhaled long-acting β2-agonist for the once daily treatment of COPD, delivered via single-dose dry powder inhaler (Onbrez® Breezhaler®). Study aims were 1) To determine absolute bioavailability (Fabs) of IND after oral inhalation compared with intravenous (IV) dosing and 2) To determine relative contributions of lung and gastrointestinal tract (GIT) absorption to systemic exposure of inhaled IND. To this end, inhaled IND was also administered concurrently with oral activated charcoal. Method: A two-part randomized, open label, single-dose study in healthy volunteers (HV). In Part 1, 8 HV received an IV infusion of 200 μg IND and an inhaled dose of 300 μg IND in a 2-way, 2-sequence crossover design. In period 3 all 8 HV received an inhaled dose of 600 μg IND together with an oral dose of charcoal. Treatments were separated by washouts of ≥14 days. In Part 2, 4 other HV received oral doses of IND (600 μg) and charcoal. Blood samples were taken for PK analysis and IND was determined in serum by LC-MS/MS. PK parameters were determined by non-compartmental methods. Results: The Fabs of inhaled IND was 45%. Oral activated charcoal was effective in blocking the oral absorption of IND. The relative bioavailability of inhaled IND with oral charcoal was 74% compared to inhalation without charcoal. Conclusion: Almost 75% of the systemic exposure following inhalation of IND was due to lung absorption, and 25% was due to GIT absorption. Based on an Fabs of 45% for inhaled IND, the fraction of the inhaled dose deposited and absorbed in the lungs was estimated as 34% of the nominal IND dose, providing evidence of effective lung delivery of inhaled IND via Onbrez® Breezhaler®.