AZD7624
Preclinical pharmacology and pharmacokinetics
AZD7624 inhibits human MAPK14 with an IC50 of 0.1nM and prevents TNFα release from human PBMCs with an IC50 of approximately 3.5nM. AZD7624 is active at both the α and β forms of p38 and is inactive at the γ and δ forms. AZD7624 was equally potent at inhibiting the rat, mouse, guinea pig, rabbit and dog recombinant p38α enzymes.
Inhaled AZD7624 is rapidly absorbed (Tmax = 5 mins) with the major route of elimination through the faeces.
Safety and tolerability
Inhaled AZD7624 has been assessed in healthy volunteers and Ph2a trials for COPD at doses ranging between 580µg to 2030µg. The mean plasma concentration profiles were characterised by rapid absorption and a decline with rapid distribution phase followed by a slower terminal elimination phase. The geometric mean terminal half-life after single inhalation of AZD7624 in the dose range 580µg to 2030µg was 34 to 72 hours.
There were no major differences in total exposure in COPD patients compared with healthy subjects receiving inhaled AZD7624. In healthy volunteers and COPD patients, no trends in laboratory parameters have been identified and no clinically significant changes were noted in ECG parameters or vital signs. Analysis of the available safety data shows that AZD7624 is generally well tolerated.
Mechanism of Action
Mitogen-activated protein kinase 14 (p38α) Inhibitor
Original Therapeutic Area
Other
CNS Penetrant
Unknown
Route of administration
Inhaled
Modality
Small Molecule
Additional Information
1. Higham A., et al. (2018).
Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells. Int J Chron Obstruct Pulmon Dis. 13:1279-1288. doi: 10.2147/COPD.S159936.
2. Patel NR., et al. (2018).
The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial. Int J Chron Obstruct Pulmon Dis. 13:1009-1019. doi: 10.2147/COPD.S150576.
3. Pehrson R., et al. (2018).
AZD7624, an Inhaled p38 Inhibitor, Demonstrates Local Lung Inhibition of LPS-Induced TNFα with Minimal Systemic Exposure. J Pharmacol Exp Ther. 365(3):567-572. doi: 10.1124/jpet.117.246132.