Phase 1 study of the safety, tolerability, and pharmacokinetics of a synthetic macrocyclic peptide antibiotic (BRII-693) in healthy adult participants.

Abstract

BRII-693 is a next-generation intravenous (IV)-administered synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This single-center, randomized, double-blind, placebo-controlled phase 1 study investigated the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of BRII-693 in 104 healthy participants. In single-dose cohorts, 10-400 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In the 7-day repeat-dose cohorts, 100-200 mg of BRII-693 was evaluated in eight participants (six active; two placebo) per cohort. In two 14-day repeat-dose cohorts, 150 mg of BRII-693 was evaluated in 12 participants (10 active, two placebo) each of non-Chinese and Chinese descent. No participant reported a severe or serious adverse event (AE) or an AE leading to death. Across all cohorts and for non-Chinese and Chinese participants, most AEs were mild. C_max and area under the concentration-time curve (AUC) increased in a dose-proportional manner over the dose range of single- and repeat-dosing. Mean t_1/2 was 2.58-4.37 hours and generally similar across single doses. An accumulation of exposure was observed following multiple doses with an accumulation ratio of 1.5 to 1.7 which was within the expected 1.3 to 2.5 range at steady state. Mean total clearance (CL) was similar between single and multiple dose administration, suggesting time-independent pharmacokinetics (PK). PK exposure was statistically equivalent between non-Chinese and Chinese participants. This phase 1 study demonstrates a favorable safety, tolerability, and PK profile of BRII-693 in healthy non-Chinese and Chinese participants.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04808414.