Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Carbapenems, ATC code: J01DH04.

Mode of action
Doripenem is a synthetic carbapenem antibacterial agent.
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death.

In vitro doripenem showed little potential to antagonise or be antagonised by other antibacterial agents. Additive activity or weak synergy with amikacin and levofloxacin has been seen for Pseudomonas aeruginosa and for gram-positive bacteria with daptomycin, linezolid, levofloxacin, and vancomycin.

Doribax PI_09 2014

Pharmacokinetic/pharmacodynamic relationship
Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of doripenem exceeds the minimum inhibitory concentration (%T>MIC) of the infecting organism has been shown to best correlate with efficacy in pre-clinical pharmacokinetic/pharmacodynamic (PK/PD) studies.
Monte Carlo simulations using pathogen susceptibility results from completed phase 3 trials and population PK data indicated that the %T>MIC target of 35% was achieved in greater than 90% of patients with nosocomial pneumonia, complicated urinary tract infections and complicated intra- abdominal infections, for all degrees of renal function.

Mechanisms of resistance
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by carbapenem-hydrolysing enzymes, mutant or acquired PBP’s, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do generally express co-resistance to doripenem. Methicillin-resistant staphylococci should always be considered as resistant to doripenem. As with other antimicrobial agents, including carbapenems, doripenem has been shown to select for resistant bacterial strains.

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

Non species related                                      S 1 mg/l and R >4 mg/l Staphylococci                                            inferred from the methicillin breakpoint Enterobacteriaceae                                       S 1 mg/l and R >4 mg/l Acinetobacter spp.                                       S 1 mg/l and R >4 mg/l Pseudomonas spp.                                         S 1 mg/l and R >4 mg/l Streptococcus spp. other than S. pneumoniae              S 1 mg/l and R >1 mg/l S. pneumoniae                                            S 1 mg/l and R >1 mg/l Enterococci                                              “inappropriate target” Haemophilus spp.                                         S 1 mg/l and R >1 mg/l N. gonorrhoeae                                           IE (insufficient evidence) Anaerobes                                                S 1 mg/l and R >1 mg/l 
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Localised clusters of infections due to carbapenem-resistant organisms have been reported in the European Union. The information below gives only approximate guidance on the probability as to whether the micro-organism will be susceptible to doripenem or not.

Commonly Susceptible Species:
Gram Positive Aerobes
Enterococcus faecalis*$
Staphylococcus aureus (methicillin susceptible strains only)*^
Staphylococcus spp. (methicillin susceptible strains only)^
Streptococcus pneumoniae*
Streptococcus spp.

Gram Negative Aerobes

Doribax PI_09 2014
            Citrobacter diversus
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae*
Haemophilus influenzae*
Escherichia coli*
Klebsiella pneumoniae*
Klebsiella oxytoca
Morganella morganii
Proteus mirabilis*
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Salmonella species
Serratia marcescens
Shigella species

Anaerobes
Bacteroides fragilis*
Bacteroides caccae*
Bacteroides ovatus
Bacteroides uniformis*
Bacteroides thetaiotaomicron*
Bacteroides vulgatus*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros*
Porphyromonas spp.
Prevotella spp.
Sutterella wadsworthenis
Species for which acquired resistance may be a problem:
Acinetobacter baumannii*
Acinetobacter spp.
Burkholderia cepacia$+
Pseudomanas aeruginosa*

Inherently resistant organisms:
Gram Positive Aerobes
Enterococcus faecium
Gram Negative Aerobes
Stenotrophomonas maltophilia
Legionella spp.
* species against which activity has been demonstrated in clinical studies $ species that show natural intermediate susceptibility
+ species with >50% acquired resistance in one or more Member State
^all methicillin-resistant staphylococci should be regarded as resistant to doripenem 

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

The mean Cmax and AUC0-∞ of doripenem in healthy subjects across studies following administration of 500 mg over 1 hour are approximately 23 g/ml and 36 g.h/ml, respectively. The mean Cmax and AUC0-∞ of doripenem in healthy subjects across studies following administration of 500 mg and 1 g over 4 hours are approximately 8 g/ml and 17 g/ml, and 34 g.h/ml and 68 g.h/ml, respectively.


Doribax PI_09 2014
There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in patients with normal renal function.

Distribution
The average binding of doripenem to plasma proteins was approximately 8.1% and is independent of plasma concentrations. The volume of distribution at steady state is approximately 16.8 L, similar to extracellular fluid volume in man. Doripenem penetrates well into several body fluids and tissues, such as uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine.

Metabolism
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via dehydropeptidase-I. Doripenem undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. In vitro studies have determined that doripenem does not inhibit or induce the activities of CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4.

Elimination
Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half- life of doripenem in healthy young adults is approximately 1 hour and plasma clearance is approximately 15.9 l/hour. Mean renal clearance is 10.3 l/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem seen with concomitant probenecid administration, suggests that doripenem undergoes glomerular filtration, tubular secretion and re- absorption. In healthy young adults given a single 500 mg dose of Doribax, 71% and 15% of the dose was recovered in urine as unchanged active substance and ring-opened metabolite, respectively.
Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy young adults, less than 1% of the total radioactivity was recovered in faeces. The pharmacokinetics of doripenem are linear over a dose range of 500 mg to 1 g when intravenously infused over either 1 or 4 hours.

Renal insufficiency
Following a single 500 mg dose of Doribax, doripenem AUC increased 1.6-fold, 2.8-fold, and 5.1-fold in subjects with mild (CrCl 51-79 ml/min), moderate (CrCl 31-50 ml/min), and severe renal impairment (CrCl 30 ml/min), respectively, compared to age-matched healthy subjects with normal renal function (CrCl >80 ml/min). AUC of the microbiologically inactive ring-opened metabolite is expected to be considerably increased in patients with severe renal impairment compared with healthy subjects. Dosage adjustment is necessary in patients with moderate and severe renal impairment (see section 4.2).

AUCs of doripenem and of the microbiologically inactive ring-opened metabolite are substantially increased in patients 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 500 mg doripenem by i.v. infusion, the amount of doripenem removed during the four-hour haemodialysis session was 231 mg (46% of the dose).

Hepatic impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of Doribax are not expected to be affected by hepatic impairment.

Elderly
The impact of age on the pharmacokinetics of doripenem was evaluated in healthy elderly male and female subjects (66-84 years of age). Doripenem AUC increased 49% in elderly adults relative to young adults. These changes were mainly attributed to age-related changes in renal function. No dosage adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency (see section 4.2).

Gender

Doribax PI_09 2014
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is recommended based on gender.

Race
The effect of race on doripenem pharmacokinetics was examined through a population pharmacokinetic analysis. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dosage adjustment is recommended for race.