Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters
Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters.
DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates.
Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71–1.42) and 0.92 (0.73–1.16) for furosemide, 1.09 (0.92–1.28) and 1.03 (0.93–1.15) for metformin, and 1.28 (1.12–1.46) and 1.21 (1.08–1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated.
Cefiderocol has no clinically significant DDI potential via drug transporters.
KeywordsCefiderocol S-649266 Siderophore cephalosporin Pharmacokinetics Drug interaction Drug transporter
We thank Yoshihisa Ozaki of Shionogi & Co., Ltd. (Osaka, Japan) and Kenneth Hawke of QPS, LLC (Newark, DE, USA) for reviewing the bioanalytical methods.
This study was funded by Shionogi.
Compliance with ethical standards
Conflict of interest
Takayuki Katsube, Shiro Miyazaki, Yukitoshi Narukawa, and Toshihiro Wajima are employees of Shionogi. Martha Hernandez-Illas conducted this research at QPS Miami Research Associates, LLC (South Miami, FL, USA) in the course of their employment, and their employers were compensated by Shionogi for conducting this study.
This study was conducted at QPS Miami Research Associates, South Miami, FL, in accordance with all appropriate regulatory requirements and under the protocol approved by an institutional review board, IntegReview IRB, Austin, TX. This study was conducted in accordance with current International Council for Harmonization (ICH) Good Clinical Practices (GCP), all appropriate subject privacy requirements, and the ethical principles outlined in the Declaration of Helsinki.
Prior to enrollment, subjects received a full explanation of the nature and the objectives of the study, the safety of the drugs under investigation, and that they were free to withdraw from the study at any time without prejudice. Prior to the initiation of any study related procedures the subjects provided written informed consent and received a copy of the signed consent form to keep as a reference.
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