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SYN-004 (ribaxamase), an oral β-lactamase designed to protect the gut microbiome from the deleterious effects of certain intravenously administered β-lactam antibiotics, degrades ceftriaxone excreted into the intestine in Phase 2a clinical studies.

著者 Kokai-Kun JF , Roberts T , Coughlin O , Sicard E , Rufiange M , Fedorak R , Carter C , Adams MH , Longstreth J , Whalen H , Sliman J この記事をPubMed上で見るPubMedで表示
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SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects including secondary infections like Clostridium difficile as well as other antibiotic-associated diarrheas. In Phase 1 clinical studies, ribaxamase was well tolerated as compared with placebo and displayed negligible systemic absorption. The two Phase 2a clinical studies described in this report were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies, to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine. (clintrials.gov NCT02419001 and NCT02473640).
PMID: 28052855 [PubMed - as supplied by publisher]
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