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Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modeling approach

Bartels, Christian, Looby, Michael, Sechaud, Romain and Kaiser, Guenther (2013) Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modeling approach. Britisch Journal of Clinical Pharmacology. ISSN 0306-5251


Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease (COPD). In this study we used population pharmacokinetic (PK) modeling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and in turn understand the impact of lung bioavailability and residence time on the choice of dosing regimen.
We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and characterize amounts of glycopyrronium in systemic compartments and lungs.
The model-derived PK parameters were comparable to those obtained with non-compartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments.
The slow absorption from the lungs, together with the rapid elimination from the systemic circulation, could explain how once-daily glycopyrronium provides sustained bronchodilation with low incidence of side effects in patients with COPD. Its extended intra-pulmonary residence time also provides pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13


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