title: Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections.
abstract: Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active-controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 μg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 μg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Suraj G
authors.initials: SG
authors.lastname: Bhansali
authors.affiliation: The University of Chicago Medicine, Section of Infectious Diseases and Global Health, Chicago, Illinois, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mullane
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Lillian S L
authors.initials: LS
authors.lastname: Ting
authors.affiliation: Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA, East Hanover, New Jersey, USA, and Cambridge, Massachusetts, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leeds
authors.affiliation: Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, East Hanover, New Jersey, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dabovic
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Praestgaard
authors.affiliation: Novartis Institutes for BioMedical Research, Infectious Disease Area, Cambridge, Massachusetts, USA peter.pertel@novartis.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Pertel
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000493:pharmacokinetics*; D014640:Vancomycin / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; D014640:Vancomycin; C573298:LFF571; D010456:Peptides, Cyclic