Pharmacotherapeutic Class: Carbapenems (ultra-broad spectrum antibiotic). ATC Code: J01DH04.
Pharmacology: Pharmacodynamics: Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However the pharmacokinetic & pharmacodynamic relationship for doripenem has not been evaluated in patients.
No significant effect on QTc interval was detected at peak plasma concentration or at any other time in healthy subjects receiving doripenem 500 mg IV every 8 hrs x 4 doses, doripenem 1g IV every 8 hrs x 4 doses, placebo and a single oral dose of positive control in a randomized, positive- and placebo-controlled crossover study.
Mechanism of Action: Doripenem belongs to the carbapenem class of antimicrobials. 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 E. Coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.
Antibacterial Spectrum: Doripenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.
Facultative gram-negative microorganisms: Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa.
Facultative gram-positive microorganisms: Streptococcus constellatus, Streptococcus intermedius.
Anaerobic microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Peptostreptococcus micros.
At least 90 percent of the following microorganisms exhibit an in vitro minimal inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for doripenem. The safety and efficacy of doripenem in treating clinical infections due to these microorganisms has not been established in adequate and well controlled clinical trials.
Facultative gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes.
Facultative gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella oxytoca, Morganella morganii, Serratia marcescens.
Mechanism(s) of Resistance: Bacterial resistance mechanisms that affect doripenem include drug 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 carbapenem hydrolyzing β-lactamases. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.
Pharmacokinetics: Mean (SD) plasma Cmax and AUC0-∞ value of doripenem were 23.0 (6.6) μg/mL and 36.3 (8.8) μg·hr/mL, respectively following a single 1-hour intravenous infusion of a 500 mg dose of doripenem to healthy subjects.
The pharmacokinetics of doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1 g when intravenously infused over 1 hour. There is no accumulation of doripenem following multiple intravenously infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function. The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09-55.5 L), similar to extracellular fluid volume (18.2 L).
Doripenem penetrates into several body fluids and tissues, including those at the site of infection for the approved indications, Doripenem concentrations in peritoneal and retroperitoneal fluid either match or exceed those required to inhibit most susceptible bacteria; however, the clinical relevance of this finding has not been established. Concentrations achieved in selected tissues and fluids following administration of doripenem are shown in Table 1: See Table 1.
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Metabolism of doripenem to a microbiologically inactive ring opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-I. The mean (SD) plasma doripenem-M1-to-doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18% (7.2%).
In pooled human liver microsomes, no in vitro metabolism of doripenem could be detected, indicating that doripenem is not a substrate for hepatic CYP450 enzymes.
Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of doripenem in healthy non-elderly adults is approximately 1 hr and mean (SD) plasma clearance is 15.9 (5.3) L/hr. Mean (SD) renal clearance is 10.8 (3.5) L/hr. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and active tubular secretion. In healthy adults given a single 500 mg dose of doripenem, a mean of 70% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hrs. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of
the total radioactivity was recovered in feces after one week.
Pharmacokinetics in Special Populations: Patients with renal impairment: Following a single 500 mg dose of doripenem for injection, the mean AUC of doripenem in subjects with mild Creatinine Clearance (CrCl 50-79 mL/min), moderate (CrCl 31-50 mL/min), and severe renal impairment (CrCl ≤30 mL/min) was 1.6-, 2.8-, and 5.1-times that of age-matched healthy subjects with normal renal function (CrCl ≥80 mL/min ), respectively. Dosage adjustment is necessary in patients with moderate and severe renal impairment.
A single 500 mg dose of doripenem was administered to subjects with end stage renal disease (ESRD) either one hour prior to or one hour after hemodialysis (HD). The mean doripenem AUC following the post-HD infusion was 7.8-times that of healthy subjects with normal renal function. The mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour HD session was 231 mg and 28 mg, respectively, or a total of 259 mg (52% of the dose). There is insufficient information to make dose adjustment recommendations in patients on hemodialysis.
Patients with 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 doripenem are not expected to be affected by hepatic impairment.
Geriatric patients: The impact of age on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects ≥66 years of age. Mean doripenem AUC0-∞ was 49% higher in elderly adults relative to non-elderly adults. This difference in exposure was mainly attributed to age-related changes in creatinine clearance. No dosage adjustment is recommended for elderly patients with normal (for their age) renal function.
Gender: The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem Cmax and AUC were similar between males and females. No dose adjustment is recommended max based on gender.
Race: The effect of race on doripenem pharmacokinetics was examined using a population pharmacokinetic analysis of data from phase 1 and 2 studies. Compared to Caucasians, mean doripenem clearance was 14% greater in Hispanic/Latino subjects whereas no difference in clearance was observed for African Americans.
Doripenem clearance in Japanese studies is similar to what has been observed in Western populations. No dosage adjustment is recommended based on race.