Effect of CYP3A4 inhibitors verapamil and itraconazole on the pharmacokinetics of AZD7986, an oral DPP1 inhibitor

Introduction: AZD7986 is an oral dipeptidyl peptidase 1 (DPP1) inhibitor originally developed for COPD and now bronchiectasis, diseases characterized by high amounts of activated neutrophils, to reduce exacerbations, improve lung function and delay disease progression. In vitro, AZD7986 is metabolised by cytochrome P450 3A isoenzymes (CYP3A) which may play a significant role in its elimination, highlighting a potential drug interaction risk. Objective: To investigate the influence on the pharmacokinetics (PK) of AZD7986 when co-administered with multiple doses of the CYP3A4 inhibitors verapamil and itraconazole or diltiazem Methods: An open-label, non-randomized, fixed sequence, 3-period study was conducted in healthy subjects. In Period 1 AZD7986 was dosed alone, in Period 2 with verapamil and in Period 3 with itraconazole or diltiazem. A washout period was included between each dosing period and an interim analysis after Period 2 to select between itraconazole and diltiazem for Period 3. Serial PK samples were taken throughout. Results: After co-dosing with verapamil, itraconazole was selected for Period 3. The following changes in PK of AZD7986, assessed as area under the curve (AUC) and maximum plasma concentration (C_max) were observed: Conclusion: The impact of co-dosing with verapamil and itraconazole on the exposure of AZD7986 was modest, suggesting that it can safely be coadministered with drugs that inhibit CYP3A4 and indicating that other clearance routes are important in the elimination of AZD7986.