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Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections

Bhansali, Suraj and Mullane, Kathleen and Ting, Lillian and Leeds, Jennifer and Dabovic, Kristina and Praestgaard, Jens and Pertel, Peter (2015) Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections. Antimicrobial Agents and Chemotherapy, 59 (3). pp. 1441-1445. ISSN 1098-6596

Abstract

Background: Clostridium difficile causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potencies against C. difficile comparable to or greater than 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.
Methods: This multi-center, randomized, evaluator-blind, 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. Drug concentrations were measured in serum and fecal samples and PK parameters were calculated.
Results: Systemic exposure following oral administration of 200 mg of LFF571 four times per day for ten days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/mL, whereas levels in the feces at the end of treatment were between 107 and 12900 µg/g. By comparison, the peak vancomycin level observed in the serum was considerably higher at 2.73 µg/mL; levels of vancomycin in the feces were not tested.
Conclusion: Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571 after ten days of dosing. These results are consistent with retention of LFF571 in the lumen of the gastrointestinal tract.

Item Type: Article
Date Deposited: 29 Apr 2016 23:45
Last Modified: 29 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/21661

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