Nonclinical Safety Assessment of SYN-004: An Oral β-lactamase for the Protection of the Gut Microbiome From Disruption by Biliary-Excreted, Intravenously Administered Antibiotics

Int J Toxicol. 2016 May;35(3):309-16. doi: 10.1177/1091581815623236. Epub 2015 Dec 23.


SYN-004 is a first in class, recombinant β-lactamase that degrades β-lactam antibiotics and has been formulated to be administered orally to patients receiving intravenous β-lactam antibiotics including cephalosporins. SYN-004 is intended to degrade unmetabolized antibiotics excreted into the intestines and thus has the potential to protect the gut microbiome from disruption by these antibiotics. Protection of the gut microbiome is expected to protect against opportunistic enteric infections such as Clostridium difficile infection as well as antibiotic-associated diarrhea. In order to demonstrate that oral SYN-004 is safe for human clinical trials, 2 Good Laboratory Practice-compliant toxicity studies were conducted in Beagle dogs. In both studies, SYN-004 was administered orally 3 times per day up to the maximum tolerated dose of the formulation. In the first study, doses of SYN-004 administered over 28 days were safe and well tolerated in dogs with the no-observed-adverse-effect level at the high dose of 57 mg/kg/day. Systemic absorption of SYN-004 was minimal and sporadic and showed no accumulation during the study. In the second study, doses up to 57 mg/kg/day were administered to dogs in combination with an intravenous dose of ceftriaxone (300 mg/kg) given once per day for 14 days. Coadministration of oral SYN-004 with intravenous ceftriaxone was safe and well tolerated, with SYN-004 having no noticeable effect on the plasma pharmacokinetics of ceftriaxone. These preclinical studies demonstrate that SYN-004 is well tolerated and, when coadministered with ceftriaxone, does not interfere with its systemic pharmacokinetics. These data supported advancing SYN-004 into human clinical trials.

Keywords: ceftriaxone; oral dosage; pharmacokinetics; toxicity; β-lactamase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / blood
  • Anti-Bacterial Agents* / pharmacokinetics
  • Bile Ducts / metabolism
  • Ceftriaxone* / administration & dosage
  • Ceftriaxone* / blood
  • Ceftriaxone* / pharmacokinetics
  • Dogs
  • Drug Interactions
  • Female
  • Gastrointestinal Microbiome
  • Male
  • Protective Agents* / administration & dosage
  • Protective Agents* / pharmacokinetics
  • Protective Agents* / pharmacology
  • Protective Agents* / toxicity
  • Recombinant Proteins* / administration & dosage
  • Recombinant Proteins* / pharmacokinetics
  • Recombinant Proteins* / pharmacology
  • Recombinant Proteins* / toxicity
  • Tablets, Enteric-Coated
  • Toxicity Tests, Subacute
  • beta-Lactamases* / administration & dosage
  • beta-Lactamases* / pharmacokinetics
  • beta-Lactamases* / pharmacology
  • beta-Lactamases* / toxicity


  • Anti-Bacterial Agents
  • Protective Agents
  • Recombinant Proteins
  • Tablets, Enteric-Coated
  • Ceftriaxone
  • SYN-004
  • beta-Lactamases