Safety, tolerability and pharmacokinetics (PK) of AZD8154 (a selective PI3K?d inhibitor) after single ascending inhaled doses in healthy volunteers

AZD8154 is an inhaled PI3Kgd inhibitor developed for treatment of asthma. This first in human study evaluate the safety, tolerability and PK of AZD8154 in healthy volunteers after inhalation of single ascending doses (Part 1) and characterized the systemic PK after an intravenous (IV) dose (Part 2). This was a randomized, single-blind, placebo-controlled and sequential group design study. In Part 1, subjects received AZD8154 target delivered doses of 0.1, 0.3, 0.9, 2.7, 5.4 and 7.7 mg via nebulisation respectively in six cohorts (6:2 active:placebo). In Part 2, 0.15 mg AZD8154 was administered IV to six subjects, after a wash-out period they were given 2.7 mg inhaled target delivered dose. Overall, single inhaled doses of AZD8154 up to target delivered dose 7.7 mg were well tolerated and no safety concerns were raised. A population PK model, using non-linear mixed effect modelling, was developed to describe the PK of AZD8154. The final PK model successfully described the trends and variability in the data. The PK of AZD8154 was characterized by an early rapid absorption phase with tmax occurring at 0.17 to 0.75 h, followed by a flat period of about 12 - 24 h, before declining in a typically mono-phasic manner. The systemic exposure of AZD8154 increased in a dose proportional manner. The terminal mean half-life was 18 to 29 h and the pulmonary bioavailability was on average 94%. In summary, AZD8154 displayed dose proportional PK characteristics in the dose range studied (0.1 to 7.7 mg) with a half-life potentially suitable for once-daily dosing and the data supports further evaluation in a multiple ascending dose study.