Azd7624, An Inhaled P38 Inhibitor, Demonstrates Local Lung Inhibition Of Lps-Induced Tnf Alpha With Minimal Systemic Exposure

Inhaled drugs generally aim to drive a local pharmacological effect in lung, at the same time minimizing systemic exposure, in order to obtain efficacy in lung disease without unwanted systemic effects. Here, we demonstrate that inhaled delivery of a p38 inhibitor (AZD7624) can provide superior pharmacokinetic exposure and superior pharmacodynamic lung effects. In rats, inhaled AZD7624 had a five times higher dose-adjusted lung exposure compared with intravenous dosing. In healthy volunteers, lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF alpha) in sputum has been shown to be significantly reduced (85%) by means of inhaled AZD7624. Here, we demonstrate that this effect is associated with a mean unbound plasma concentration, gained from in vitro and ex vivo LPS-challenge protocols, significantly below potencies obtained for AZD7624, suggesting that lung exposure is probably much higher than systemic exposure. This assessment was made for the unbound potency (plC(50)u), e.g., the potency remaining after adjustment for plasma protein binding and blood plasma ratio. Hence, the unbound potency of AZD7624 to inhibit LPS-induced TNF alpha in human mononuclear cells, in whole blood as well as in alveolar macrophages in vitro, was 8.4,8.7 (full inhibition), and 9.0 (partial inhibition), respectively. The plC(50)u in whole blood ex vivo was 8.8, showing good in vitro/in vivo potency correlations. Thus, a mean unbound AZD7624 plasma concentration of 0.3 nmol/l, which was associated with a decrease in LPS-induced sputum TNF alpha by 85%, is much lower than the plC(50)u. This demonstrates that AZD7624 can achieve significant local lung pharmacodynamic effects with concomitant sub-pharmacological systemic exposure.