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
Autor: | Michael J. Schlosser, J. Andrew Bristol, John F. Kokai-Kun, John Setser |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Male medicine.drug_class 030106 microbiology Cephalosporin Antibiotics Administration Oral Pharmacology Biology Toxicology Protective Agents beta-Lactamases 03 medical and health sciences Dogs Pharmacokinetics medicine Animals Drug Interactions Gastrointestinal Microbiome Ceftriaxone Clostridium difficile Recombinant Proteins Anti-Bacterial Agents Diarrhea Toxicity Tests Subacute Toxicity Administration Intravenous Female Bile Ducts Tablets Enteric-Coated medicine.symptom medicine.drug |
Zdroj: | International journal of toxicology. 35(3) |
ISSN: | 1092-874X |
Popis: | 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. |
Databáze: | OpenAIRE |
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