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Antimicrob Agents Chemother. 2019 Jul 1. pii: AAC.00892-19. doi: 10.1128/AAC.00892-19. [Epub ahead of print]

Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, An Intravenous Potentiator, After Single and Multiple Ascending Doses and When Combined with Beta-Lactam Antibiotics in Healthy Subjects.

Author information

1
Spero Therapeutics, Cambridge, MA peckburg@sperotherapeutics.com.
2
Spero Therapeutics, Cambridge, MA.
3
Pfizer Inc., New York, NY.
4
E. Sullivan and Associates, LLC, Newburyport, MA.
5
CMAX Clinical Research and Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia.
6
Acceleron Pharma, Cambridge, MA.

Abstract

SPR741 is a novel polymyxin B derivative with minimal intrinsic antibacterial activity and reduced non-clinical nephrotoxicity compared to polymyxin B that interacts with the outer membrane of Gram-negative bacteria enhancing penetration of co-administered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in 2 studies, after single and multiple intravenous (IV) doses in healthy adult subjects and after co-administration with partner antibiotics. In the single and multiple ascending dose study, SPR741 or placebo was administered as a 1-hour infusion at single doses of 5-800 mg and multiple doses of 50-600 mg q8h for 14 days. In the drug-drug interaction study, a single 400 mg IV dose of SPR741 was administered alone and in combination with piperacillin/tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using non-compartmental analysis. After single doses, a dose-linear and proportional increase in mean Cmax and AUC was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 hours post-dose. After multiple doses, mean half-life was 2.2 hours on Day 1 and up to 14.0 hours on Day 14 with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with co-administration. SPR741 was generally well tolerated at doses up to 1800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria.

PMID:
31262767
DOI:
10.1128/AAC.00892-19
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