Pharmacology: Pharmacodynamics: Mechanism 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.
doripenem showed little potential to antagonize or be antagonized 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.
Similar to other β-lactam antimicrobial agents, the time that the plasma concentration of doripenem exceeds the MIC (%T>MIC) of the infecting organism has been shown to best correlate with efficacy in preclinical 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 >90% of patients with nosocomial pneumonia, complicated urinary tract infections and complicated intra-abdominal infections, for all degrees of renal function.
Extending the infusion time of Doribax to 4 hrs maximizes the %T>MIC for a given dose and is the basis for the option to administer 4-hr infusions in patients with nosocomial pneumonia including ventilator-associated pneumonia. In seriously ill patients or those with an impaired immune response, a 4-hr infusion time may be more suitable when the MIC of doripenem for the known or suspected pathogen(s) has been shown or is expected to be >0.5 mg/L, in order to reach a target attainment of 50% T>MIC in at least 95% of the patients. Monte Carlo simulations supported the use of 500 mg 4-hr infusions every 8 hrs in subjects with normal renal function for target pathogens with doripenem MICs ≤4 mg/L.
Mechanisms of Resistance:
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most β-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolyzing β-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.
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows: See table.
Click on icon to see table/diagram/image
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.
Localized clusters of infections due to carbapenem-resistant organisms have been reported in the European Union. The information as follows gives only approximate guidance on the probability as to whether the microorganism will be susceptible to doripenem or not.
Commonly Susceptible Species:
Gram-positive Aerobes: Enterococcus faecalis1,2
, Staphylococcus aureus
(methicillin-susceptible strains only)1,4
spp (methicillin-susceptible strains only)4
, Streptococcus pneumoniae1
Gram-negative Aerobes: Citrobacter diversus
, Citrobacter freundii
, Enterobacter aerogenes
, Enterobacter cloacae1
, Haemophilus influenzae1
, Escherichia coli
, Klebsiella pneumoniae1
, Klebsiella oxytoca
, Morganella morganii
, Proteus mirabilis1
, Proteus vulgaris
, Providencia rettgeri
, Providencia stuartii
spp, Serratia marcescens
Anaerobes: Bacteroides fragilis1
, Bacteroides caccae1
, Bacteroides ovatus
, Bacteroides uniformis1
, Bacteroides thetaiotaomicron1
, Bacteroides vulgatus1
, Bilophila wadsworthia
, Peptostreptococcus micros1
spp, Sutterella wadsworthenis
Species for which acquired resistance may be a problem: Acinetobacter baumannii1
spp, Burkholderia cepacia2,3
, Pseudomonas aeruginosa1
Inherently Resistant Organisms:
Gram-positive Aerobes: Enterococcus faecium
Gram-negative Aerobes: Stenotrophomonas maltophilia
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.
The mean Cmax
of doripenem in healthy subjects across studies following administration of 500 mg over 1 hr are approximately 23 mcg/mL and 36 mcg·hr/mL, respectively. The mean Cmax
of doripenem in healthy subjects across studies following administration of 500 mg and 1 g over 4 hrs are approximately 8 mcg/mL and 17 mcg/mL and 34 mcg·hr/mL and 68 mcg·hr/mL, respectively. There is no accumulation of doripenem following multiple IV infusions of either 500 mg or 1 g administered every 8 hrs for 7-10 days in patients with normal renal function.
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 eg, uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine.
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via dehydropeptidase-I. Doripenem undergoes little to no cytochrome P-450 (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.
Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-life of doripenem in healthy young adults is approximately 1-hr and plasma clearance is approximately 15.9 L/hr. Mean renal clearance is 10.3 L/hr. 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 reabsorption. 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, <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 IV infused over either 1 or 4 hrs.
Following a single 500-mg dose of Doribax, doripenem AUC increased 1.6-, 2.8- 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 Dosage & Administration).
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 6 subjects with end stage renal disease on haemodialysis received a single dose of 500-mg doripenem by IV infusion, the amount of doripenem removed during the 4-hr haemodialysis session was 231 mg (46% of the dose).
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 is not expected to be affected by hepatic impairment.
The impact of age on the pharmacokinetics of doripenem was evaluated in healthy elderly male and female subjects (66-84 years). Doripenem AUC increased by 49% in the elderly 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 Dosage & Administration).
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 dosage adjustment is recommended based on gender.
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.
Toxicology: Preclinical Safety Data:
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity. However, because of the design of the repeat dose toxicity studies and differences in pharmacokinetics in animals and humans, continuous exposure of animals was not assured in these studies.
No reproductive toxicity was observed in studies performed in rats and rabbits. However, these studies are of limited relevance because studies were performed with single daily dosing resulting in <1/10 of daily doripenem exposure duration in animals.