Pharmacokinetics and safety of fidaxomicin in patients with inflammatory bowel disease and Clostridium difficile infection: An open-label Phase IIIb/IV study (PROFILE)

Mahida, Yashwant; Stallmach, Andreas; Marteau, Philippe; Rydzewska, Grazyna; Ivashkin, Vladimir; Gargalianos-Kakolyris, Panagiotis; Michon, Ingrid; Adomakoh, Nicholas; Georgopali, Areti; Tretter, Reiner; Karas, Andreas; Reinisch, Walter; Högenauer, Christoph

Abstract

©The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. Objectives Inflammatory bowel disease (IBD) poses an increased risk for Clostridium difficile infection (CDI). Fidaxomicin has demonstrated non-inferiority to vancomycin for initial clinical cure of CDI in patients without IBD; however, lack of data has caused concerns regarding potential systemic absorption of fidaxomicin in patients with IBD. Methods The plasma pharmacokinetics (PK) of fidaxomicin and its primary metabolite OP-1118 were evaluated in a multicentre, open-label, single-arm, Phase IIIb/IV study enrolling patients with active IBD and CDI. Patients received fidaxomicin, 200 mg twice daily for 10 days. The primary and secondary endpoints were, respectively, plasma and stool PK of fidaxomicin and OP-1118 on Days 1, 5 and 10 of treatment. Other secondary endpoints included safety of fidaxomicin treatment (assessed until Day 180). ClinicalTrials.gov identifier: NCT02437591. Results Median T max of fidaxomicin and OP-1118 for the PK analysis set (PKAS; 24 patients) was 1-2 h across Days 1, 5 and 10. C max ranges were 1.2-154 ng/mL for fidaxomicin and 4.7-555 ng/mL for OP-1118 across Days 1, 5 and 10 (PKAS). The ranges of concentrations in stool were 17.8-2170 μg/g for fidaxomicin and 0-1940 μg/g for OP-1118. Sixty percent (15/25) of patients experienced treatment-emergent adverse events (TEAEs), none of which led to treatment discontinuation or death. Conclusions Maximum fidaxomicin and OP-1118 plasma concentrations observed in this study population suggest no increase in absorption, compared with patients without IBD. Incidence of TEAEs was similar to previous Phase III trials, suggesting that fidaxomicin is comparatively well tolerated in patients with IBD.

Citation

Mahida, Y., Stallmach, A., Marteau, P., Rydzewska, G., Ivashkin, V., Gargalianos-Kakolyris, P., …Högenauer, C. (2018). Pharmacokinetics and safety of fidaxomicin in patients with inflammatory bowel disease and Clostridium difficile infection: An open-label Phase IIIb/IV study (PROFILE). Journal of Antimicrobial Chemotherapy, 73(12), 3430-3441. https://doi.org/10.1093/jac/dky368

• Journal Article Type: Article
• Acceptance Date: Aug 17, 2018
• Online Publication Date: Sep 27, 2018
• Publication Date: Dec 1, 2018
• Deposit Date: Oct 5, 2018
• Publicly Available Date: Oct 5, 2018
• Journal: Journal of Antimicrobial Chemotherapy
• Print ISSN: 0305-7453
• Electronic ISSN: 1460-2091
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 73
• Issue: 12
• Pages: 3430-3441
• DOI: https://doi.org/10.1093/jac/dky368
• Keywords: Pharmacology (medical); Pharmacology; Infectious Diseases
• Public URL: https://nottingham-repository.worktribe.com/output/1148057
• Publisher URL: https://academic.oup.com/jac/article/73/12/3430/5107803