Modelling of lung pharmacokinetics of NVA237: efficient deposition, sustained lung concentrations and limited systemic exposure

C Bartels2, M Looby2, P Colthorpe2, R Sechaud1, G Kaiser1. 1Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, 2Novartis Pharma AG, CH-4002 Basel, Switzerland

Introduction: Lung pharmacokinetics of glycopyrronium bromide (NVA237), a once-daily long-acting muscarinic antagonist used for the treatment of chronic obstructive pulmonary disease (COPD), was modelled based on plasma pharmacokinetics (PK) of glycopyrronium from a study in healthy volunteers. Previous clinical studies have demonstrated that once-daily glycopyrronium has a rapid onset of action and sustained 24-hour efficacy. The study used to build our model investigated the absolute bioavailability of inhaled glycopyrronium delivered via the Breezhaler® device in comparison with i.v. administration and characterized the contribution of pulmonary absorption to systemic exposure. To this end, glycopyrronium 200 µg was inhaled with or without concomitant oral administration of activated charcoal. Plasma concentrations of glycopyrronium were available up to 72 hours post dose from 20 healthy volunteers after i.v. administration of glycopyrronium 120 µg and from 18 healthy volunteers after inhalation of glycopyrronium with or without charcoal. The model provides a detailed description of lung and plasma pharmacokinetics and provides the basis for simulations.

Methods: Lung PK were inferred by contrasting plasma PK of glycopyrronium after an i.v. infusion to plasma pharmacokinetics after inhalation with concomitant administration of activated charcoal, and were modelled with compartments attributed to the lung. The model was used to carry out simulations of different regimens and to characterize amounts of drug in systemic and in lung compartments.

Result: Of the glycopyrronium that passed through the lung into systemic circulation, about 80% had sustained retention in the lung and was transferred to systemic circulation with a half-life approaching 80 h. The remaining 20% was rapidly absorbed with a half-life of less than 1 h. Independent of whether simulating a once-daily or twice-daily dosing regimen, at PK steady state more than 90% of glycopyrronium was in lung compartments and less than 10% was in systemic compartments.

Conclusion: Modelling supports that glycopyrronium has favourable PK properties with sustained retention and prolonged transfer from the lung, rapid clearance from systemic circulation and a large fraction of the drug being in compartments associated with the lung. These findings provide additional pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug.