Chemical formula: C₃₀H₃₄ClN₇O₁₀S₂ Molecular mass: 752.21 g/mol
Cefiderocol is a siderophore cephalosporin. In addition to passive diffusion through outer membrane porin channels, cefiderocol is able to bind to extracellular free iron via its siderophore side chain, allowing active transport into the periplasmic space of Gram-negative bacteria through siderophore uptake systems. Cefiderocol subsequently binds to penicillin binding proteins (PBPs), inhibiting bacterial peptidoglycan cell wall synthesis which leads to cell lysis and death.
Mechanisms of bacterial resistance that may lead to resistance to cefiderocol include mutant or acquired PBPs; beta-lactamase enzymes with ability to hydrolyse cefiderocol; mutations affecting regulation of bacterial iron uptake; mutations in siderophore transport proteins; overexpression of native bacterial siderophores.
The in vitro antibacterial activity effect of cefiderocol against normally susceptible species is not affected by the majority of beta-lactamases, including metallo-enzymes. Due to the siderophore-mediated mode of cell entry, the in vitro activity of cefiderocol activity is generally less affected by porin loss or efflux-mediated resistance compared to many other beta-lactam agents.
Cefiderocol has little or no activity against Gram-positive or anaerobic bacteria due to intrinsic resistance.
In vitro studies demonstrated no antagonism between cefiderocol and amikacin, ceftazidime/avibactam, ceftolozane/tazobactam, ciprofloxacin, clindamycin, colistin, daptomycin, linezolid, meropenem, metronidazole, tigecycline, or vancomycin.
After multiple dose administration of cefiderocol, there is no accumulation of cefiderocol administered every 8 hours in healthy adult subjects with normal renal function.
The binding of cefiderocol to human plasma proteins, primarily albumin, is in the range of 40 to 60%, the geometric mean (CV%) volume of distribution during the terminal phase of cefiderocol in healthy adult subjects (n=43) after intravenous administration of a single 2 g dose of cefiderocol was 18.0 L (18.1%), similar to extracellular fluid volume.
After administration of a single 1 g dose of [14C]-labelled cefiderocol infused over 1 hour, cefiderocol accounted for 92.3% of the plasma AUC for total radioactivity. The most predominant metabolite, pyrrolidine chlorobenzamide (PCBA, which is a degradation product of cefiderocol), accounted for 4.7% of the plasma AUC for total radioactivity, while other more minor metabolites each accounted for <2% of the plasma AUC for total radioactivity.
Co-administration with 2 g doses of cefiderocol given every 8 hours did not affect the pharmacokinetics of midazolam (a CYP3A substrate), furosemide (a OAT1 and OAT3 substrate) or metformin (a OCT1, OCT2, and MATE2-K substrate). Co-administration with 2 g doses of cefiderocol given every 8 hours increased rosuvastatin (a OATP1B3 substrate) AUC by 21%, which was considered not to be clinically meaningful.
The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. The geometric mean (CV) of clearance of cefiderocol in healthy subjects is estimated to be 5.18 (17.2) L/hr. Cefiderocol is primarily eliminated by the kidneys. After administration of a single 1 g dose of [14C]-labelled cefiderocol infused over 1 hour, the amount of total radioactivity excreted in urine was 98.6% of the administered dose, with 2.8% of the administered dose excreted in faeces. The amount of unchanged cefiderocol excreted in urine was 90.6% of the administered dose.
Cefiderocol exhibits linear pharmacokinetics within the dose range of 100 mg to 4000 mg.
In a population pharmacokinetic analysis, no clinically relevant effect on the pharmacokinetics of cefiderocol was observed with respect to age, gender or race.
Pharmacokinetic studies have not been performed with cefiderocol in infants and children under 18 years of age.
The pharmacokinetics of cefiderocol after administration of a single 1 g dose was assessed in subjects with mild renal impairment (n=8, estimated glomerular filtration rate [eGFR] of 60 to <90 mL/min/1.73 m²), moderate renal impairment (n=7, eGFR 30 to <60 mL/min/1.73 m²), severe renal impairment (n=6, eGFR less than 30 mL/min/1.73 m²), end-stage renal disease (ESRD) requiring haemodialysis (n=8), and healthy subjects with normal renal function (n=8, estimated creatinine clearance of at least 90 mL/min). The geometric mean ratios (GMR; mild, moderate, severe or ESRD without haemodialysis/normal renal function) and 90% confidence intervals (CI) for the AUC of cefiderocol were 1.0 (0.8, 1.3), 1.5 (1.2, 1.9), 2.5 (2.0, 3.3) and 4.1 (3.3, 5.2), respectively. Approximately 60% of cefiderocol was removed by a 3- to 4-hour haemodialysis session.
The recommended dose adjustments in subjects with varying degrees of renal impairment are expected to provide comparable exposures to subjects with normal renal function or mild renal impairment.
Simulations using the population PK model demonstrated that the recommended dose adjustment for ARC provide exposures, including %T>MIC, of cefiderocol comparable to those in patients with normal renal function.
Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represent a minor pathway of elimination of cefiderocol.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, or genotoxicity. Carcinogenicity studies with cefiderocol have not been conducted.
Cefiderocol was negative for mutagenicity in an in vitro reverse mutation test with bacteria and in the in vitro HPRT gene mutation assay in human cells. Positive findings were seen in an in vitro chromosomal aberration test in cultured TK6 cells and an in vitro mouse lymphoma assay (MLA). There was no evidence of in vivo genotoxicity (rat micronucleus assay and comet assay in rats).
Cefiderocol had no impairment of fertility and early embryonic development in rats treated with cefiderocol intravenously up to 1000 mg/kg/day corresponding to a margin to clinical exposure of 0.8. There was no evidence of teratogenicity or embryotoxicity in rats or mice that received 1000 mg/kg/day or 2000 mg/kg/day respectively corresponding to margins to clinical exposure of 0.9 and 1.3.
Cefiderocol had no adverse effects on growth and development, including neurobehavioural function in juvenile rats that received 1000 mg/kg/day subcutaneously during postnatal day (PND)7 to PND27, or 600 mg/kg/day intravenously from PND28 to PND48.
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