Doripenem

Doripenem (common name doripenem monohydrate) is an ultra-broad spectrum injectable antibiotic. It is a beta-lactam and belongs to the subgroup of carbapenems. It was launched by Shionogi Co. of Japan under the brand name Finibax in 2005 and is being marketed outside Japan by Johnson & Johnson. It is particularly active against Pseudomonas aeruginosa.

Doripenem can be used for bacterial infections such as: complex abdominal infections, pneumonia within the setting of a hospital, and complicated infections of the urinary tract including kidney infections with septicemia. Primarily, doripenem decreases the process of cell wall growth, which eventually leads to elimination of the infectious cell bacteria altogether.

It is recommended that those allergic to doripenem or to any type of beta-lactam antibiotics such as cephalosporin or other Carbapenems not receive doripenem.

Doripenem was approved by the United States Food and Drug Administration on October 12, 2007, to be sold under the tradename Doribax.^[1]

Chemistry and Pharmacology

Doripenem is a beta-lactam antibiotic agent belonging to the carbapenem group, with a broad spectrum of bacterial sensitivity. Although doripenem may be quite similar to other related carbapenem agents, the antibiotic includes several divergent properties. For example, doripenem includes a transfiguration of hydroxyethyl group, and in position 4 there is a carbon atom. These differences make the agent more stable against other pathogens. Doripenem inhibits renal dehydropeptidase-1 hydrolysis due to its structure containing a single side chain, 1-beta methyl. Additionally, within the molecular structure a sulfamoylaminomethyl-pyrrolindinylthio group is attached to a side chain giving the molecule increased antibacterial action against gram-negative microbes. In vivo, doripenem inhibits the synthesis of cell walls by attaching itself to penicillin binding proteins, also known as PBPs.

Physicochemical Properties

Doripenem appears as crystalline powder anywhere from a white to somewhat yellowish colour.Doripenem is moderately soluble in water, slightly soluble in methanol, and virtually insoluble in ethanol. Doripenem is also solution in N,N-dimethylformamide. Doripenem is composed of a 6 asymmetrical carbon molecule and is most commonly displayed by one pure isomer. In terms of doripenem for injection, the crystallized powered drug can form a monohydrate when mixed with water. However, Doripenem has not been proven to possess polymorphism.

Resistance

Potential avenues for the development of resistance to doripenem are: altered PBPs (penicillin binding protein), activity in the permeability of the outer membrane being reduced especially when accepting foreign toxic substances within the cell, and hydrolyzing enzymes from the carbapenem deactivating the drug from functioning. Beta-lactamases (such as penicillinases) formed by gram-positive and gram-negative bacteria can stabilize doripenem to hydrolysis. However, carbapenem hydrolyzing beta-lactamases are an exception.

Pharmacokinetics

Distribution

On average, about 8.1% of plasma proteins attached to doripenem; it is separate from drug concentrations of plasma.^[2] Doripenem’s distribution volume is close to that of extracellular fluid volume in humans (18.2 L). When doripenem is essentially stable the average volume of distribution is approximately 16.8 L. Within the few of the body’s fluids and tissues, Doripenem is filtered successfully as well as reach concentration levels that are able to restrain from more vulnerable bacteria than what is required.

Metabolism

Doripenem is metabolized by the enzyme dehydropeptidase-I into an inactive ring-opened metabolite.

Excretion

In young and healthy adults, the elimination half-life of doripenem considering the average plasma terminal is normally around 1 hour. The plasma clearance is about 15.9L/hour and the average renal clearance is 10.3 L/hour. Research indicates doripenem is filtered by the glomerular capillary bed in Bowman’s capsule and the tubular secretions in the nephron.

References

1. ^ "FDA Approves New Drug to Treat Complicated Urinary Tract and Intra-Abdominal Infections" (Press release). U.S. Food and Drug Administration. October 17, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01728.html. Retrieved 2007-10-25. 
2. ^ "Doripenem for Injection for the Treatment of Nosocomial Pneumonia" (Press release). Johnson & Johnson. July 16, 2008. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4364b1-02-Johnson.pdf. Retrieved 2010-05-19. 

2. Janssen-Ortho Inc. (September 1, 2009) "Doribax". Retrieved November 22,2009. http://www.janssen-ortho.com/JOI/pdf_files/Doribax_E.pdf

3. Chemical Process Research and Development. American Chemical Society. (September 24, 2003) "Practical Large-Scale Synthesis of Doripenem: A Novel 1β-Methylcarbapenem Antibiotic". Retrieved November 22, 2009. http://pubs.acs.org/doi/abs/10.1021/op034088n

4. European Medicines Agency. (2008) "CHMP Assessment Report for Doribax". Retrieved November 22, 2009. http://www.emea.europa.eu/humandocs/PDFs/EPAR/doribax/H-891-en6.pdf

5. Formulary Journal Vol. 42 (December 2007)"Doripenem: A new extended-spectrum carbapenem antibiotic". Retrieved November 26, 2009. http://web.ebscohost.com/ehost/pdf?vid=8&hid=4&sid=8ccb7619-3d37-431f-bf13-d0ddc9ffc481%40sessionmgr114

6. Drugs R & D (2003) "Doripenem: S 4661". Retrieved November 23, 2009. http://web.ebscohost.com/ehost/pdf?vid=14&hid=106&sid=ee346c2a-d844-4d2b-a065-bdd8e7bf2348%40sessionmgr4