Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other cephalosporins and penems, ATC code: J01DI54.

Mechanism of action

Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell-wall synthesis and subsequent cell death.
Tazobactam is a beta-lactam structurally related to penicillins. It is an inhibitor of many molecular Class A beta-lactamases, including CTX-M, SHV, and TEM enzymes. See below.

Mechanisms of resistance

Mechanisms of bacterial resistance to ceftolozane/tazobactam include: i.   Production of beta-lactamases that can hydrolyse ceftolozane and which are not inhibited by tazobactam (see below) ii.  Modification of PBPs

Tazobactam does not inhibit all Class A enzymes.
In addition tazobactam does not inhibit the following types of beta-lactamase: i.      AmpC enzymes (produced by Enterobacterales) ii.     Serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs]) iii.    Metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase [NDM]) iv.     Ambler Class D beta-lactamases (OXA-carbapenemases)

Pharmacokinetic/pharmacodynamic relationships

For ceftolozane the time that the plasma concentration exceeds the minimum inhibitory concentration of ceftolozane for the infecting organism has been shown to be the best predictor of efficacy in animal models of infection.

For tazobactam the PD index associated with efficacy was determined to be the percentage of the dose interval during which the plasma concentration of tazobactam exceeds a threshold value (%T > threshold). The time above a threshold concentration has been determined to be the parameter that best predicts the efficacy of tazobactam in in vitro and in vivo non-clinical models.

Susceptibility testing breakpoints

Minimum inhibitory concentration breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:


Minimum Inhibitory
Concentrations (mg/L)
Pathogen                    Type of Infection                                     Susceptible  Resistant Enterobacterales            Complicated intra-abdominal infections*                   ≤2            >2 Complicated urinary tract infections*
Acute pyelonephritis*
Hospital-acquired pneumonia, including ventilator-associated pneumonia**
P. aeruginosa               Complicated intra-abdominal infections*                    ≤4               >4 Complicated urinary tract infections*
Acute pyelonephritis*
Hospital-acquired pneumonia, including ventilator-associated pneumonia**
H. influenzae               Hospital-acquired pneumonia, including                    ≤ 0.5            > 0.5 ventilator-associated pneumonia**
*Based on 1 g ceftolozane / 0.5 g tazobactam intravenously every 8 hours.
**Based on 2 g ceftolozane / 1 g tazobactam intravenously every 8 hours.

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens listed under each indication that were susceptible to Zerbaxa in vitro:


Complicated intra-abdominal infections
Gram-negative bacteria
Enterobacter cloacae
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa

Gram-positive bacteria
Streptococcus anginosus
Streptococcus constellatus
Streptococcus salivarius

Complicated urinary tract infections, including pyelonephritis
Gram-negative bacteria
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis

Hospital-acquired pneumonia, including ventilator-associated pneumonia 
Gram-negative bacteria
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
Serratia marcescens

Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to Zerbaxa in the absence of acquired mechanisms of resistance: Citrobacter freundii
Citrobacter koseri
Klebsiella (Enterobacter) aerogenes
Morganella morganii
Proteus vulgaris
Serratia liquefaciens

In vitro data indicate that the following species are not susceptible to ceftolozane/tazobactam: Staphylococcus aureus
Enterococcus faecalis
Enterococcus faecium

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The Cmax and AUC of ceftolozane/tazobactam increase approximately in proportion to dose within ceftolozane single-dose range of 250 mg to 3 g and tazobactam single-dose range of 500 mg to 1.5 g. No appreciable accumulation of ceftolozane/tazobactam is observed following multiple 1-hour IV infusions of 1 g / 0.5 g ceftolozane/tazobactam or 2 g / 1 g ceftolozane/tazobactam administered every 8 hours for up to 10 days in healthy adults with normal renal function. The elimination half-life (t½) of ceftolozane or tazobactam is independent of dose.

Distribution

The binding of ceftolozane and tazobactam to human plasma proteins is low (approximately 16% to 21% and 30%, respectively). The mean (coefficient of variation CV%) steady-state volume of distribution of ceftolozane/tazobactam in healthy adult males (n=51) following a single 1 g / 0.5 g IV dose was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume.

Following 1 hour intravenous infusions of 2 g / 1 g ceftolozane/tazobactam or adjusted based on renal function every 8 hours in ventilated adult patients with confirmed or suspected pneumonia (N=22), ceftolozane and tazobactam concentrations in pulmonary epithelial lining fluid were greater than 8 mcg/mL and 1 mcg/mL, respectively, over 100% of the dosing interval. Mean pulmonary epithelial-to-free plasma AUC ratios of ceftolozane and tazobactam were approximately 50% and 62%, respectively and are similar to those in healthy adult subjects (approximately 61% and 63%, respectively) receiving 1 g / 0.5 g ceftolozane/tazobactam.

Biotransformation

Ceftolozane is eliminated in the urine as unchanged parent substance and thus does not appear to be metabolised to any appreciable extent. The beta-lactam ring of tazobactam is hydrolysed to form the pharmacologically inactive, tazobactam metabolite M1.

Elimination

Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single 1 g / 0.5 g IV dose of ceftolozane/tazobactam to healthy male adults greater than 95% of ceftolozane was excreted in the urine as unchanged parent substance. More than 80% of tazobactam was excreted as the parent compound with the remaining amount excreted as the tazobactam M1 metabolite.
After a single dose of ceftolozane/tazobactam, renal clearance of ceftolozane (3.41 - 6.69 L/h) was similar to plasma clearance (4.10 - 6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration.

The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 hours and 1 hour, respectively.

Linearity/non-linearity

The Cmax and AUC of ceftolozane/tazobactam increase in proportion to dose. Plasma levels of ceftolozane/tazobactam do not increase appreciably following multiple IV infusions of up to 2.0 g / 1.0 g administered every 8 hours for up to 10 days in healthy adults with normal renal function. The elimination half-life (t½) of ceftolozane is independent of dose.

Special populations

Renal impairment
Ceftolozane/tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys.
The ceftolozane dose normalised geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in adults with mild, moderate, and severe renal impairment, respectively, compared to healthy adults with normal renal function. The respective tazobactam dose normalised geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain similar systemic exposures to those with normal renal function, dose adjustment is required (see section 4.2).

In adults with end stage renal disease on haemodialysis, approximately two-thirds of the administered ceftolozane/tazobactam dose is removed by haemodialysis. The recommended dose in adults with end stage renal disease on haemodialysis with complicated intra-abdominal infections or complicated urinary tract infections (including acute pyelonephritis) is a single loading dose of 500 mg / 250 mg ceftolozane/tazobactam followed by a 100 mg / 50 mg maintenance dose of ceftolozane/tazobactam administered every 8 hours for the 
remainder of the treatment period. With haemodialysis, the dose should be administered immediately following completion of dialysis (see section 4.2).

Augmented renal clearance
Following a single 1-hour intravenous infusion of 2 g / 1 g ceftolozane/tazobactam to critically ill adults with CrCL greater than or equal to 180 mL/min (N=10), mean terminal half-life values of ceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively. Free plasma ceftolozane concentrations were greater than 8 mcg/mL over 70% of an 8-hour period; free tazobactam concentrations were greater than 1 mcg/mL over 60% of an 8-hour period. No dose adjustment of ceftolozane/tazobactam is recommended for hospital- acquired pneumonia, including ventilator-associated pneumonia in adults with augmented renal clearance.

Hepatic impairment
As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance of ceftolozane/tazobactam is not expected to be affected by hepatic impairment. No dose adjustment is recommended for ceftolozane/tazobactam in subjects with hepatic impairment (see section 4.2).

Elderly
In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in exposure were observed with regard to age. No dose adjustment of ceftolozane/tazobactam based on age alone is recommended.

Paediatric patients
Zerbaxa is not indicated for children and adolescents under 18 years old.

Gender
In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed for ceftolozane and tazobactam. No dose adjustment is recommended based on gender.

Ethnicity
In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in ceftolozane/tazobactam AUC were observed in Caucasians compared to other ethnicities. No dose adjustment is recommended based on race.