Pre-clinical to clinical potency of AZD7624 in LPS induced TNFa response

Abstract

AZD7624 is an inhaled p38 inhibitor being developed for COPD. Here we used LPS challenge in i) in vitro blood derived mononuclear cells (MC) and alveolar macrophages (AM), ii) ex vivo human blood and iii) in vivo inhaled LPS in order to determine both the translatability of unbound potency (nM) between methods and if the effect of AZD7624 in the lung (potency) versus systemic potency is enhanced by inhalation.

In vitro, cells were pretreated with AZD7624 prior to LPS. Ex-vivo, human blood was obtained from subjects having inhaled AZD7624, prior to LPS. In vivo, rats were given inhaled AZD7624 at different doses at different time-points prior to an inhaled LPS challenge. TNFa was determined in lung lavage. Healthy volunteers were given inhaled AZD7624 prior to inhaled LPS, followed by sputum induction in which TNFa was measured.

In vitro, the potency was 4 nM (human MC and whole blood) and 3-7/0.5 nM (rat/human, AM). Ex-vivo, the potency was 2 nM when AZD7624 was given by inhalation. In vivo in rats, inhaled AZD7624 decreased lung TNFa response to inhaled LPS with mean plasma concentrations <0.5 nM. In vivo in human, inhaled AZD7624 decreased lung TNFa response by 85% to inhaled LPS with mean plasma concentrations ∼1 nM.

In different models, there is a consistency with similar potencies of AZD7624. The in vivo potency of inhaled AZD7624 on LPS induced TNFa in lungs tends to be higher than on LPS induced TNFa in vitro and ex-vivo in blood. This implies that inhalation of AZD7624 (and thus higher local exposure) provides a benefit by an increased local anti-inflammatory effect compared to oral delivery systemic activity.