Pharmacokinetic interactions of azithromycin and ethambutol with or without SPR720 in healthy participants

ABSTRACT SPR720 is an aminobenzimidazole prodrug that is rapidly converted in vivo to SPR719, an inhibitor of the DNA gyrase B ATPase subunit in mycobacteria. SPR719 demonstrates potent in vitro activity against clinically relevant Mycobacterium avium complex (MAC) species. This study evaluated the pharmacokinetics (PK), safety, and tolerability of SPR720, azithromycin, and ethambutol administered alone and in combination in healthy adults. Participants were assigned to one of five groups and received the following oral regimens daily for 7 days: (1) SPR720 1,000 mg, (2) azithromycin 500 mg, (3) ethambutol 800 mg, (4) SPR720 plus azithromycin and ethambutol, or (5) azithromycin plus ethambutol. PK and safety analyses included 39 participants. Between-group PK comparisons were descriptive, and no formal statistical hypothesis testing was performed. On Day 7, mean SPR719 AUC 0– τ was 15% higher with SPR720 plus azithromycin and ethambutol than with SPR720 alone, indicating a modest difference in SPR719 exposure. Azithromycin exposure increased from Day 1 to Day 7, consistent with its long half-life. On Day 7, mean azithromycin AUC 0– τ was 56% higher with azithromycin plus ethambutol than with azithromycin alone but was 47% lower with the three-drug regimen than with azithromycin plus ethambutol. Mean ethambutol AUC 0– τ was 19% lower with azithromycin plus ethambutol and 48% lower with the three-drug regimen than with ethambutol alone. Macrolides remain the cornerstone of MAC pulmonary disease (MAC-PD) therapy. These descriptive findings highlight the importance of evaluating PK within multidrug regimens for MAC-PD rather than extrapolating from single- or dual-agent studies. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT05966688 .