Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters
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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.
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.
- 1.Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, Rhomberg PR, Jones RN, Yoshizawa H, Nakamura R, Tsuji M, Yamano Y (2016) In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting gram-negative bacteria. J Antimicrob Chemother 71:670–677CrossRefPubMedGoogle Scholar
- 2.Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, Rittenhouse S, Tsuji M, Yamano Y (2015) In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother 60:729–734CrossRefPubMedGoogle Scholar
- 3.Matsumoto S, Singley CM, Hoover J, Nakamura R, Echols R, Rittenhouse S, Tsuji M, Yamano Y (2017) Efficacy of cefiderocol against carbapenem-resistant gram-negative bacilli in immunocompetent-rat respiratory tract infection models recreating human plasma pharmacokinetics. Antimicrob Agents Chemother 61:e00700–e00717CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Portsmouth S, Veenhuyzen D, Echols R, Machida M, Arjona Ferreira JC, Ariyasu M, Nagata T (2017) Abstr 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), abstr ECCMD-7582. Cefiderocol Compared with Imipenem/Cilastatin in the Treatment of Adults with Complicated Urinary Tract Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis: Results from a Multicenter, Double-blind, Randomized Study (APEKS-cUTI)Google Scholar
- 7.Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA, Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism/Clinical Pharmacology Technical Working Group; FDA Center for Drug Evaluation and Research (CDER) (2003) The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815–832CrossRefPubMedGoogle Scholar
- 8.US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2017) In vitro metabolism- and transporter-mediated drug-drug interaction studiesGoogle Scholar
- 9.US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2017) Clinical drug interaction studies—study design, data analysis, and clinical implicationsGoogle Scholar
- 10.European Medicines Agency (2012) Guideline on the investigation of drug interactionsGoogle Scholar
- 11.FDA, Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s). ZERBAXA. Application Number: 206829Orig1s000Google Scholar
- 14.Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP. 1995. Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide. Br J Clin Pharmacol 39:692–695Google Scholar
- 18.Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R (2017) Pharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function. Antimicrob Agents Chemother 61:e01381-16, e01381, e01316Google Scholar