Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease.

Aims This 3-part, randomised, phase 1 first-in-human study (NCT03436316) investigated the safety, tolerability and pharmacokinetics (PK) of AZD8154, a dual phosphoinositide 3-kinase (PI3K) γδ inhibitor developed as a novel inhaled anti-inflammatory treatment for respiratory disease. Methods Healthy men, and women of nonchildbearing potential, were enrolled to receive single and multiple ascending inhaled doses of AZD8154 in parts 1 and 3 of the study, respectively, while part 2 characterised the systemic PK after a single intravenous (IV) dose. In part 1, participants received 0.1-7.7 mg AZD8154 in 6 cohorts. In part 2, participants were given 0.15 mg AZD8154 as an IV infusion. In part 3, AZD8154 was given in 3 cohorts of 0.6, 1.8 and 3.1 mg, with a single dose on Day 1 followed by repeated once-daily doses on Days 4-12. Results In total, 78 volunteers were randomised. All single inhaled, single IV and multiple inhaled doses were shown to be well tolerated without any safety concerns. A population PK model, using nonlinear mixed-effect modelling, was developed to describe the PK of AZD8154. The terminal mean half-life of AZD8154 was 18.0-32.0 hours. The geometric mean of the absolute pulmonary bioavailability of AZD8154 via the inhaled route was 94.1%. Conclusion AZD8154 demonstrated an acceptable safety profile, with no reports of serious adverse events and no clinically significant drug-associated safety concerns reported in healthy volunteers. AZD8154 demonstrated prolonged lung retention and a half-life supporting once-daily dosing.