Cefepime exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis as a result of binding to and inhibition of penicillin-binding proteins (PBPs). Cefepime is generally stable to hydrolysis by class C AmpC and class D OXA-48 enzymes.
Enmetazobactam is a penicillanic acid sulfone beta-lactamase inhibitor structurally related to penicillin. Enmetazobactam binds to β-lactamases and prevents the hydrolysis of cefepime. It is active against class A ESBLs. Enmetazobactam does not reliably inhibit the class A carbapenemase KPC and does not inhibit class B, class C or class D beta-lactamases.
Bacterial resistance mechanisms that could potentially affect cefepime-enmetazobactam include mutant or acquired PBPs, decreased outer membrane permeability to either compound, active efflux of either compound, and β-lactamase enzymes refractory to inhibition by enmetazobactam and able to hydrolyse cefepime.
No antagonism was demonstrated in in vitro medicinal product combination studies with cefepimeenmetazobactam and azithromycin, aztreonam, clindamycin, daptomycin, doxycycline, gentamicin levofloxacin, linezolid, metronidazole, trimethoprim-sulfamethoxazole, or vancomycin.
The antimicrobial activity of cefepime has been shown to best correlate with the percentage of time of the dosing interval in which the free active substance concentration was above the cefepimeenmetazobactam MIC (% fT >MIC). For enmetazobactam, the pharmacokinetic/pharmacodynamic (PK-PD) index is the percentage of time of the dosing interval in which the free active substance concentration was above a threshold concentration (% fT >CT).
After intravenous (IV) administration of 2 g cefepime and 0.5 g enmetazobactam over 2 hours to patients with cUTI q8h, peak plasma concentrations (Cmax) assessed on Day 1 and Day 7 were 87–100 mcg/ml and 17–20 mcg/ml for cefepime and enmetazobactam respectively.
There was no significant difference in Cmax and AUC between healthy volunteers and cUTI patients in the population PK analysis.
Cefepime and enmetazobactam are well distributed in bodily fluids and tissues including bronchial mucosa. Based on the population PK analysis, the total volume of distribution was 16.9 L for cefepime and 20.6 L for enmetazobactam.
The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum. For enmetazobactam the serum protein binding is negligible.
An epithelial lining fluid (ELF) study in healthy volunteers showed that cefepime and enmetazobactam have similar lung penetration up to 73% and 62% at 8 hours post start of infusion, respectively, with a biodistribution coefficient fAUC (ELF/plasma) over the entire 8h dosing interval of 47% for cefepime and 46% for enmetazobactam.
Cefepime is metabolised to a small extent. The primary metabolite is N-methylpyrrolidine (NMP) which accounts for approximately 7% of the administered dose.
Enmetazobactam undergoes minimal hepatic metabolism.
Both cefepime and enmetazobactam are primarily excreted via kidneys as unchanged substance.
The mean elimination half-life of cefepime 2 g and enmetazobactam 500 mg when administered in combination in cUTI patients were 2.7 hours and 2.6 hours, respectively.
Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. For enmetazobactam, approximately 90% of the dose was excreted unchanged in the urine over a 24-hour period. Mean renal clearance for enmetazobactam was 5.4 L/h and mean total clearance was 8.1 L/h.
There is no accumulation of cefepime or enmetazobactam following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function.
Themaximum plasma concentration (Cmax) and area under the plasma active substance concentration time curve (AUC) of cefepime and enmetazobactam proportionally increased with dose across the dose range studied (1 gram to 2 grams for cefepime and 0.6 grams to 4 grams for enmetazobactam) when administered as a single intravenous infusion.
Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men and women. Safety and efficacy in elderly patients was comparable to that in adults, while the elimination half-life was slightly longer and renal clearance lower in elderly patients. Dose adjustment is necessary in elderly patients with reduced renal function.
Population PK analysis for enmetazobactam did not demonstrate any clinically relevant change in PK parameters in elderly patients.
For cefepime, without dose adjustment AUC0-inf is approximately 1.9-fold, 3-fold, and 5-fold higher for subjects with mild, moderate, and severe renal impairment, respectively compared with subjects with normal renal function and 12-fold higher for subjects with ESRD who underwent dialysis before cefepime-enmetazabactam administration compared with subjects with normal renal function.
For enmetazobactam, without dose adjustment AUC0-inf is approximately 1.8-fold, 3-fold, 5-fold higher for subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function and 11-fold higher for subjects with ESRD who underwent dialysis before cefepime-enmetazabactam administration compared with subjects with normal renal function.
To maintain similar systemic exposures to those with normal renal function, dose adjustment is required.
The average elimination half-life in haemodialysis volunteers (n=6), after dosing was 23.8 hours and 16.5 hours for cefepime and enmetazobactam, respectively. With haemodialysis, the dose should be administered immediately following completion of dialysis. Haemodialysis increased systemic clearance in subjects with ESRD when dialysis was performed after dosing (clearance 2.1 L/h and 3.0 L/h for cefepime and enmetazobactam, respectively) compared to values when dialysis was performed before dosing (clearance for cefepime and enmetazobactam 0.7 L/h and 0.8 L/h, respectively).
For cefepime the half life was 19 hours for continuous ambulatory peritoneal dialysis.
Simulations using the population PK model demonstrated that patients with supra-normal creatinine clearance (>150 mL/min) had a 28% decrease of systemic exposure compared to patients with normal renal function (80-150 mL/min). In this population, based on pharmacokinetic/pharmacodynamic considerations, prolongation of duration of infusion to 4 hours is recommended to maintain appropriate systemic exposure.
With single-dose administration of 1 g, the kinetics of cefepime was unchanged in patients with hepatic impairement.
Enmetazobactam undergoes minimal hepatic metabolism and has a low potential for altered PK in the presence of hepatic impairment. Thus, no dose adjustment is required.
The pharmacokinetics of cefepime-enmetazobactam has not yet been evaluated in patients from birth to 18 years old.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity or genotoxicity. No long term studies were performed in the animal to assess the carcinogenic potential.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology or genotoxicity. Carcinogenicity studies with enmetazobactam have not been conducted.
Dose dependent liver findings in terms of hepatocellular accumulation of glycogen accompanied by increases in liver weights in rats and by single cell cystic degeneration/necrosis and increased cholesterol and liver enzyme levels in dogs were observed following 28 days of once daily intravenous administration of enmetazobactam alone.
The liver effects induced by enmetazobactam did not change or exacerbate when given together with cefepime. Following up to 4 weeks (in rats) and 13 weeks (in dogs) of once daily intravenous administration of enmetazobactam and cefepime, corresponding adverse liver effects (at least partially reversible) were observed at 250/500 mg/kg/day in rats (AUC0-24 195 mcg*h/mL) and at 200/400 mg/kg/day in dogs (AUC0-24 639 mcg*h/mL). These doses result in an exposure margin of 0.86-fold in rats and 2.8-fold in dogs compared to the exposure at the maximum recommended human dose (AUC0-24 226 mcg*h/mL). At the NOAELs of 125/250 mg/kg/day in rats and 50/100 mg/kg/day in dogs the margin to the exposure at the maximum recommended human dose was 0.57-fold and 0.71-fold, respectively.
In reproductive toxicity of enmetazobactam in rat and rabbit, delayed skeletal ossification (localised to the skull) were recorded in both rat and rabbit. Increased post-implantation loss, lower mean foetal weight and skeletal changes (sternum with fused sternebrae) were recorded in rabbit. These effects were observed together with maternal toxicity and at clinically relevant doses. Thus, NOAEL for rat is 250 mg/kg/day and for rabbit 50 mg/kg/day with a margin to the exposure at maximum recommended human dose of 1.14-fold and 1.10-fold, respectively.
In a peri-postnatal study on rat, lower pup weight, a slight delay in the pre-weaning development and reduced motor activity for a few males during the maturation phase were observed in the F1 generation. No abnormalities were seen in pups culled on Day 4 post partum, with exception of hindlimb lesions (rotation of paw and/or swollen paw), which were recorded in 2 pups from different litters in the F2 generation at 500 mg/kg/day. NOAEL for the F1 generation were 125 mg/kg/day and for maternal toxicity and F2 development 250 mg/kg/day, with a margin to the exposure at maximum recommended human dose of 0.68-fold and 1.14-fold, respectively.
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