Prediction of human lung PK for AZD7624, an inhaled P38 inhibitor for the treatment of COPD

Abstract

Inhibition of p38 mitogen-activated protein kinases has been suggested as novel treatment for COPD. However, since p38 has high expression in tissues other than lung, local delivery may be crucial for an effective treatment while reducing potential unwanted side effects driven by systemic exposure. AZD7624 is a novel P38 inhibitor designed for inhaled administration for COPD. Here we examined the lung and plasma pharmacokinetic (PK) profile of AZD7624 in a rat inhalation model to predict human PK profile, which was validated in a human single ascending dose study.

Rats were administrated a single dose of AZD7624 either through dry powder inhalation or intravenously. Lung tissue and plasma samples were taken up to 80 hours post dose for PK determination. AZD7624 (29, 101, 336, 631, and 1177 µg single lung deposited dose) was administrated by inhalation to healthy volunteers and plasma samples were takenfor PK determination.

In the rat a long terminal half life in the lung of approximately 60 hours was observed. The ratio between lung and plasma concentration following inhalation was ∼500-1000 times during 24h while IV administration resulted in ∼10 times lower lung-plasma ratio.

The human plasma PK parameters were comparable across all doses, and characterized by a rapid absorption followed by a fast distribution phase and a long terminal half-life (64 - 72 h). The human plasma PK was in good agreement with the prediction based on the rat PK, and supports the prediction of a high lung concentration in man. Hence, AZD7624 appears to have promising PK properties for inhaled treatment of COPD.