Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium
Pharmacotherapeutic group: Antibacterials for systemic use, Carbapenems
ATC code: J01DH04
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.
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 III 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.
Extending the infusion time of Doribax to 4 hours maximises the % T>MIC for a given dose and is the basis for the option to administer 4-hour infusions in patients with nosocomial pneumonia including ventilator-associated pneumonia. In seriously ill patients or those with an impaired immune response, a 4-hour 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 (see section 4.2). Monte Carlo simulations supported the use of 500 mg 4-hour infusions every 8 hours in subjects with normal renal function for target pathogens with doripenem MICs ≤ 4 mg/l.
Bacterial resistance mechanisms that effect doripenem include active substance inactivation by carbapenem-hydrolysing enzymes, mutant or acquired PBPs, 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.
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 |
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.
Gram-positive aerobes:
Enterococcus faecalis*$
Staphylococcus aureus (methicillin susceptible strains only)*@
Staphylococcus spp. (methicillin susceptible strains only)@
Streptococcus pneumoniae*
Streptococcus spp.
Gram-negative aerobes:
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 spp.
Serratia marcescens
Shigella spp.
Anaerobes
Bacteroides fragilis*
Bacteroides caccae*
Bacteroides ovatus
Bacteroides uniformis*
Bacteroides thetaiotaomicron*
Bacteroides vulgatus*
Bilophila wadsworthia
Peptostreptococcus magnus
Peptostreptococcus micros*
Porphyromonas spp.
Prevotella spp.
Sutterella wadsworthensis
Acinetobacter baumannii*
Acinetobacter spp.
Burkholderia cepacia$+
Pseudomonas aeruginosa*
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
Ventilator-associated pneumonia:
A study of 233 patients with late-onset VAP failed to demonstrate the non-inferiority of an investigational 7-day course of doripenem (1 g every 8 hours as a 4 hour infusion) compared to a 10-day course of imipenem/cilastatin (1 g every 8 hours as a 1 hour infusion). In addition, the patients were allowed to receive specified adjunctive therapies. The study was stopped early based on the recommendation of an independent data monitoring committee. The clinical cure rate at the end of treatment visit on day 10 was numerically lower for subjects in the doripenem arm of the primary microbiological intent-to-treat (MITT) (45.6% versus 56.8%; 95% CI: -26.3%; 3.8%) and co-primary microbiologically evaluable (ME) (49.1% [28/57] versus 66.1% [39/59]); 95% CI: -34.7%; 0.8%) analysis sets. The overall 28-day all cause mortality rate was numerically higher for doripenem treated subjects in the MITT analysis set (21.5% versus 14.8%; 95% CI: -5.0%; 18.5%).The difference in clinical cure rate between doripenem versus imipenem/cilastatin was greater in patients with APACHE score > 15 (16/45 [36%] versus 23/46 [50%]) and in patients infected with Pseudomonas aeruginosa 7/17 [41%] versus 6/10 [60%]).
The mean Cmax and AUC0-∞ of doripenem in healthy subjects across studies following administration of 500 mg over 1 hour are approximately 23 μg/ml and 36 µg.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 µg/ml and 17 µg/ml, and 34 µg.h/ml and 68 µg.h/ml, respectively. 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 subjects with normal renal function.
Doripenem single dose pharmacokinetics after a 4-hour infusion in adults with cystic fibrosis are consistent with those in adults without cystic fibrosis. Adequate and well controlled studies to establish the safety and efficacy of doripenem in patients with cystic fibrosis have not been conducted.
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 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.
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 2 g when intravenously infused over 1 hour and 500 mg to 1 g when intravenously infused over 4 hours.
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 (doripenem-M-1) is expected to be considerably increased in patients with severe renal impairment compared with healthy subjects. Dose adjustment is necessary in patients with moderate and severe renal impairment (see section 4.2).
Doribax dosage adjustment is necessary in patients receiving continuous renal replacement therapy (see section 4.2). In a study where 12 subjects with end stage renal disease received a single 500 mg dose of doripenem as a 1-hour i.v. infusion, the systemic exposure to doripenem and doripenem-M-1 were increased compared with healthy subjects. The amount of doripenem and doripenem-M-1 removed during a 12-hour CVVH session was approximately 28% and 10% of the dose, respectively; and during a 12-hour CVVHDF session was approximately 21% and 8% of the dose, respectively. Dosing recommendations for patients on continuous renal replacement therapy were developed to achieve doripenem systemic exposures similar to subjects with normal renal function who receive doripenem 500 mg as a 1-hour infusion, to maintain doripenem concentrations above a minimum inhibitory concentration of 1 mg/l for at least 35% of the dosing interval, and to maintain doripenem and doripenem-M-1 metabolite exposures below those observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. These dosing recommendations were derived by modeling data from subjects with end stage renal disease receiving continuous renal replacement therapy, and take into consideration the potential increases in non-renal clearance of carbapenems in patients with acute renal insufficiency compared to patients with chronic renal impairment. Doripenem-M-1 had a slow elimination in the patient group and the half-life (and AUC) has not been satisfactorily determined. Therefore, it may not be excluded that the exposure obtained in patients receiving continuous renal replacement therapy will be higher than estimated and thus higher than metabolite exposures observed with a 1-hour infusion of 1 g doripenem every 8 hours in healthy subjects. The in vivo consequences of the increased exposures to the metabolite are unknown as data on pharmacological activity, except for antimicrobiological activity, are lacking (see section 4.4). If the doripenem dose is increased beyond the recommended dose for continuous renal replacement therapy, the systemic exposure of the doripenem-M-1 metabolite is even further increased. The clinical consequences of such an increase in exposure are unknown.
The systemic exposures to doripenem and doripenem-M-1 are substantially increased in patients with end stage renal disease receiving haemodialysis compared with healthy subjects. In a study where six subjects with end stage renal disease received a single dose of 500 mg doripenem by i.v. infusion, the amount of doripenem and doripenem-M-1 removed during a 4-hour haemodialysis session was approximately 46% and 6% of the dose, respectively. There is insufficient information to make dose adjustment recommendations in patients on intermittent haemodialysis or dialysis methods other than continuous renal replacement therapy (see section 4.2).
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.
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 dose adjustment is necessary in elderly patients, except in cases of moderate to severe renal insufficiency (see section 4.2).
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 13% higher in females compared to males. No dose 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 dose adjustment is recommended for race.
Non-clinical 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 less than one tenth of daily doripenem exposure duration in animals.
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