Chemical formula: C₂₀H₂₂N₈O₆S₂ Molecular mass: 690.66 g/mol
Ceftobiprole exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs) in susceptible species. In Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Ceftobiprole binds to PBP2a. Ceftobiprole has demonstrated in vitro activity against strains with divergent mecA homolog (mecC or mecALGA251). Ceftobiprole also binds to PBP2b in Streptococcus pneumoniae (penicillin-intermediate), PBP2x in S. pneumoniae (penicillin resistant), and to PBP5 in Enterococcus faecalis.
Ceftobiprole is inactive against strains of Enterobacteriaceae that express Ambler class A β-lactamases, especially TEM, SHV and CTX-M type extended-spectrum β-lactamases (ESBL) and the KPC-type carbapenemases, Ambler class B β-lactamases and Ambler class D β-lactamases, especially ESBL variants and carbapenemases (OXA-48). Ceftobiprole is also inactive against strains that have high levels of expression of Ambler class C β-lactamases.
Ceftobiprole is inactive against strains of P. aeruginosa that express enzymes belonging to Ambler class A (e.g. PSE-1), Ambler class B (e.g. IMP-1, VIM-1, VIM-2) and Ambler class D (e.g. OXA-10). It is also inactive against isolates that have acquired mutations in regulatory genes leading to de-repressed levels of expression of the chromosomal Ambler class C β-lactamase, or over-expression of the Mex XY efflux pump.
Ceftobiprole is inactive against strains of Acinetobacter spp. that express enzymes belonging to Ambler class A (e.g. VEB-1), Ambler class B (e.g. IMP-1, IMP-4) Ambler class D (e.g. OXA-25, OXA-26), or that have de-repressed levels of expression of the chromosomal Ambler class C β-lactamase.
The mean pharmacokinetic parameters of ceftobiprole medocaril in adults for a single 500 mg dose administered as a 2-hour infusion and multiple 500 mg doses administered every 8 hours as 2-hour infusions are summarised in Table 1. Pharmacokinetic characteristics were similar with single and multiple dose administration.
Mean (standard deviation) pharmacokinetic parameters of ceftobiprole medocaril in adults:
| Parameter | Single 500 mg dose administered as a 120 minute infusion | Multiple 500 mg doses administered every 8 hours as 120 minute infusions |
|---|---|---|
| Cmax (μg/mL) | 29.2 (5.52) | 33.0 (4.83) |
| AUC (μg• h/mL) | 90.0 (12.4) | 102 (11.9) |
| t1/2 (hours) | 3.1 (0.3) | 3.3 (0.3) |
| CL (l/h) | 4.89 (0.69) | 4.98 (0.58) |
Ceftobiprole binds minimally (16%) to plasma proteins and binding is independent of concentration. Ceftobiprole steady-state volume of distribution (18 litres) approximates extracellular fluid volume in humans.
The active substance of ceftobiprole medocaril is ceftobiprole medocaril sodium, which is the pro-drug of the active moiety ceftobiprole. Conversion from the prodrug ceftobiprole medocaril sodium, to the active moiety ceftobiprole, occurs rapidly and is mediated by non-specific plasma esterases. Prodrug concentrations are negligible and are measurable in plasma and urine only during infusion. The metabolite resulting from the cleavage of the prodrug is diacetyl which is an endogenous human compound.
Ceftobiprole undergoes minimal metabolism to the open-ring metabolite, which is microbiologically inactive. Systemic exposure of the open-ring metabolite was considerably lower than for ceftobiprole, accounting for approximately 4% of the parent exposure in subject with a normal renal function.
In vitro studies demonstrated that ceftobiprole is an inhibitor of the hepatocyte uptake transporters OATP1B1 and OATP1B3, but is not an inhibitor of PgP, BCRP, MDR1, MRP2, OAT1, OAT3, OCT1 or OCT2. Ceftobiprole is potentially a weak substrate of the renal tubule cells uptake transporters OAT1 and OCT2.
Ceftobiprole protein binding is low (16%) and is not a PgP inhibitor or substrate. The potential for other drugs to interact with ceftobiprole is minimal, since only a small fraction of ceftobiprole is metabolised. Therefore, no relevant drug-drug interactions are anticipated.
Since ceftobiprole does not undergo tubular secretion and only a fraction is reabsorbed, renal drug-drug interactions are not expected.
Ceftobiprole is eliminated primarily unchanged by renal excretion, with a half-life of approximately 3 hours. The predominant mechanism responsible for elimination is glomerular filtration, with some active reabsorption. Following single dose administration in human, approximately 89% of the administered dose is recovered in the urine as active ceftobiprole (83%), the open-ring metabolite (5%) and ceftobiprole medocaril (<1%).
Ceftobiprole exhibits linear and time-independent pharmacokinetics. The Cmax and AUC of ceftobiprole medocaril increase in proportion to dose over a range of 125 mg to 1 g. Steady-state active substance concentrations are attained on the first day of dosing; no appreciable accumulation occurs with every-8-hour dosing in subjects with normal renal function.
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of ceftobiprole medocaril exceeds the minimum inhibitory concentration of the infecting organism (%T>MIC) has been shown to best correlate with efficacy in clinical and pre-clinical pharmacokinetic/pharmacodynamic studies.
The estimation of creatinine clearance should be based on the Cockcroft-Gault formula using actual body weight. During treatment with ceftobiprole it is recommended that an enzymatic method of measuring serum creatinine be used.
The pharmacokinetics of ceftobiprole are similar in healthy volunteers and subjects with mild renal impairment (CLCR 50 to 80 mL/min). Ceftobiprole AUC was 2.5- and 3.3-fold higher in subjects with moderate (CLCR 30 to <50 mL/min) and severe (CLCR <30 mL/min) renal impairment, respectively, than in healthy subjects with normal renal function. Dosage adjustment is recommended in patients with moderate to severe renal impairment.
AUCs of ceftobiprole and of the microbiologically inactive ring-opened metabolite are substantially increased in patients with end stage renal disease who require haemodialysis compared with healthy subjects. In a study where six subjects with end stage renal disease on haemodialysis received a single dose of 250 mg ceftobiprole medocaril by intravenous infusion, ceftobiprole was demonstrated haemodialysable with an extraction ratio of 0.7.
Ceftobiprole systemic clearance (CLSS) was 40% greater in subjects with a CLCR >150 mL/min compared to subjects with a normal renal function (CLCR = 80-150 mL/min). Volume of distribution was 30% larger. In this population, based on pharmacokinetic/pharmacodynamic considerations, prolongation of duration of infusion is recommended.
The pharmacokinetics of ceftobiprole in patients with hepatic impairment have not been established. As ceftobiprole undergoes minimal hepatic metabolism and is predominantly excreted unchanged in the urine, the clearance of ceftobiprole medocaril is not expected to be affected by hepatic impairment.
Population pharmacokinetic data showed that age as an independent parameter has no effect on the pharmacokinetics of ceftobiprole. Dosage adjustment is not considered necessary in elderly patients with normal renal function.
Systemic exposure to ceftobiprole was higher in females than males (21% for Cmax and 15% for AUC), however the %T>MIC was similar in both males and females. Therefore, dosage adjustments based on gender are not considered necessary.
Population pharmacokinetic analyses (including Caucasians, Black and Other groups) and a dedicated pharmacokinetic study in healthy Japanese subjects showed no effect of race on the pharmacokinetics of ceftobiprole. Therefore, dosage adjustments based on race are not considered necessary.
A study was performed in morbidly obese subjects. No dose adjustments based on body weight are required.
Reversible renal toxicity in the distal tubules due to precipitation of drug-like material was observed at high doses only in small animals such as rats and marmosets and after bolus administration. Absence of kidney toxicity was observed in animals at urinary concentrations up to 12 times higher than those observed in humans at the therapeutic dose. Convulsions were observed after both single and multiple doses at exposures of six times the human exposure and higher, based on Cmax.
Infusion-site irritation leading to thrombus formation was observed in small animals (rats and marmosets) but not in dogs. In a pre- and post-natal development study in rats, litter size and survival up to 4 days postpartum were decreased at maternally toxic doses. The relevance of all these findings for humans is unknown.
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