Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.

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.