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Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.
Eur J Clin Pharmacol. 2018 Jul; 74(7):931-938.EJ

Abstract

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

Cefiderocol has no clinically significant DDI potential via drug transporters.

Authors+Show Affiliations

Clinical Pharmacology & Pharmacokinetics, Shionogi & Co., Ltd., Osaka, Japan. takayuki.katsube@shionogi.co.jp.Drug Metabolism & Pharmacokinetics Department, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.Project Management Department, Shionogi & Co., Ltd., Osaka, Japan.QPS Miami Research Associates, South Miami, FL, USA.Clinical Pharmacology & Pharmacokinetics, Shionogi & Co., Ltd., Osaka, Japan.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

29627897

Citation

Katsube, Takayuki, et al. "Drug-drug Interaction of Cefiderocol, a Siderophore Cephalosporin, Via Human Drug Transporters." European Journal of Clinical Pharmacology, vol. 74, no. 7, 2018, pp. 931-938.
Katsube T, Miyazaki S, Narukawa Y, et al. Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters. Eur J Clin Pharmacol. 2018;74(7):931-938.
Katsube, T., Miyazaki, S., Narukawa, Y., Hernandez-Illas, M., & Wajima, T. (2018). Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters. European Journal of Clinical Pharmacology, 74(7), 931-938. https://doi.org/10.1007/s00228-018-2458-9
Katsube T, et al. Drug-drug Interaction of Cefiderocol, a Siderophore Cephalosporin, Via Human Drug Transporters. Eur J Clin Pharmacol. 2018;74(7):931-938. PubMed PMID: 29627897.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters. AU - Katsube,Takayuki, AU - Miyazaki,Shiro, AU - Narukawa,Yukitoshi, AU - Hernandez-Illas,Martha, AU - Wajima,Toshihiro, Y1 - 2018/04/07/ PY - 2018/01/28/received PY - 2018/03/27/accepted PY - 2018/4/9/pubmed PY - 2018/10/13/medline PY - 2018/4/9/entrez KW - Cefiderocol KW - Drug interaction KW - Drug transporter KW - Pharmacokinetics KW - S-649266 KW - Siderophore cephalosporin SP - 931 EP - 938 JF - European journal of clinical pharmacology JO - Eur. J. Clin. Pharmacol. VL - 74 IS - 7 N2 - PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Cefiderocol has no clinically significant DDI potential via drug transporters. SN - 1432-1041 UR - https://www.unboundmedicine.com/medline/citation/29627897/Drug_drug_interaction_of_cefiderocol_a_siderophore_cephalosporin_via_human_drug_transporters_ L2 - https://dx.doi.org/10.1007/s00228-018-2458-9 DB - PRIME DP - Unbound Medicine ER -