Doripenem

Identification

Summary

Doripenem is an antibiotic of the penem class used to treat complicated intra-abdominal and urinary tract infections.

Generic Name

Doripenem

DrugBank Accession Number

DB06211

Background

Doripenem is a broad-spectrum, carbapenem antibiotic marketed under the brand name Doribax by Janssen. Doripenem injection was approved by the FDA in 2007 to treat complicated urinary tract and intra-abdominal infections. In a clinical trial of doripenem treatment in ventilator associated pneumonia (vs. imipenem and cilastatin), it was found that doripenem carried an increased risk of death and lower clinical cure rates, resulting in a premature termination of the trial. The FDA revised the doripenem label in 2014 to include a warning against use in ventilator-associated pneumonia and to reiterate its safety and efficacy for its approved indications.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 420.504
Monoisotopic: 420.1137259
Chemical Formula: C₁₅H₂₄N₄O₆S₂

Synonyms

Doripenem

External IDs

S 4661
S-4661

Pharmacology

Indication

Doripenem is indicated in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, caused by designated susceptible bacteria.

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC (T>MIC) of the infecting organism has been shown to best correlate with efficacy in animal models of infection.

Mechanism of action

Doripenem is a broad-spectrum carbapenem antibiotic with activity against many gram-positive and gram-negative aerobic bacteria, as well as a variety of anaerobes. Like other beta-lactam antibiotics, doripenem's bactericidal mechanism of action is mostly due to cell death after inhibition of bacterial enzymes called penicillin-bindng proteins (PBPs), which are responsible for peptidoglycan cross-linking during the synthesis of the bacterial cell wall. Carbapenems mainly have high affinity for PBPs 1a, 1b, 2 and 3. Inhibition of each PBP usually results in a different inactivating mechanism. Inhibition of PBPs 1a and 1b results in fast bacterial killing through the formation of spheroplasts, inhibition of PBP 2 results in rod-shaped bacteria to become spherical, and inhibition of PBP 3 results in filamentous-shaped organisms. The PBPs preferentially bound by different carbapenems depend on the organism. 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. Doripenem has a 1-beta-methyl side chain, which allows it to be relatively resistant to dehydropeptidase, as well as a trans-alpha-1-hydroxyethyl group at position 6 which provides beta-lactamase resistance. Like other carbapenems, doripenem is different from most beta-lactams due to its stability against hydrolysis by most beta-lactamases, including penicillinases, cephalosporinases, ESBL, and Amp-C producing enterobacteriaceae.

Target	Actions	Organism
APenicillin-binding protein 1A	antagonist inhibitor	Escherichia coli (strain K12)
APenicillin-binding protein 1B	antagonist inhibitor	Escherichia coli (strain K12)
APenicillin-binding protein 2	antagonist inhibitor	Escherichia coli (strain K12)
APenicillin-binding protein 3	antagonist inhibitor	Pseudomonas aeruginosa
APenicillin-binding protein 4	antagonist inhibitor	Staphylococcus aureus

Absorption

Doripenem is administered intravenously as an infusion. There was no accumulation of doripenem following mulitiple infusions of either 500mg or 1g administered every 8 hours for 7-10 days in subjects with normal renal function.

Volume of distribution

The average Vd is 16.8 L (8.09-55.5 L) at steady-state in healthy subjects. Doripenem penetrates into many tissues and fluids, including potential sites of approved indication infections.

Protein binding

8.1%

Metabolism

Metabolism of doripenem is via dehydropeptidase-I (also called dipeptidase-1) into a microbiologically inactive ring-opened metabolite, doripenem-M1. Doripenem does not appear to be a substrate of the hepatic CYP450 enzymes.

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Doripenem
- doripenem-M1

Route of elimination

Doripenem is primarily eliminated unchanged by the kidneys and undergoes glomerular filtration and active tubular secretion. A mean of 71% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours of 500 mg dose in healthy adults. 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.

Half-life

1 hour, in healthy non-elderly adults.

Clearance

10.3 L/hour.

Adverse Effects

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Toxicity

Dosage adjustment is necessary in patients with moderate and severe renal impairment.

Doripenem's FDA label includes a warning against use in ventilator-associated bacterial pneumonia, as a clinical trial for that indication resulted in increased mortality with doripenem (23% vs. 16.7% recieving imipenem) as well as lower clinical response rates.

Seizures have been reported with doripenem treatment; patients at greater risk of developing seizures we found to have pre-existing central nervous system (CNS) conditions, compromised renal function, or patients receiving higher doses than 500 mg every 8 hours. Doripenem also reduces plasma levels of valproic acid when administered concomitantly; therefore patients with pre-existing seizure disorders on valproic acid are at even higher risk of breakthrough seizures if receiving both drugs at the same time.

Doripenem is considered pregnancy category B as it was not found to be teratogenic or produce effects on ossification, developmental delays, or fetal weight in rat and rabbit studies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. It is not known whether doripenem is excreted into breast milk, therefore caution should be exercised with doripenem administration to nursing women.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Doripenem which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Doripenem which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Doripenem which could result in a higher serum level.
Acenocoumarol	The risk or severity of bleeding can be increased when Doripenem is combined with Acenocoumarol.
Acetaminophen	Acetaminophen may decrease the excretion rate of Doripenem which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Doripenem which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acid	The excretion of Doripenem can be decreased when combined with Acetylsalicylic acid.
Aclidinium	Doripenem may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Acrivastine	Doripenem may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Acyclovir	The excretion of Doripenem can be decreased when combined with Acyclovir.

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Food Interactions

No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Doripenem hydrate	4B035T6NKT	364622-82-2	NTUBEBXBDGKBTJ-WGLOMNHJSA-N

International/Other Brands

Finibax (Shionogi Co.)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Doribax	Powder, for solution	250 mg/10mL	Intravenous	SHIONOGI INC.	2010-10-15	2020-02-28
Doribax	Powder, for solution	500 mg/10mL	Intravenous	Ortho-McNeil-Janssen Pharmaceuticals Inc.	2007-10-12	2011-02-28
Doribax	Injection, powder, for solution	500 mg	Intravenous	Janssen Cilag International Nv	2016-09-08	2014-10-17
Doribax	Powder, for solution	500 mg/10mL	Intravenous	SHIONOGI INC.	2007-10-12	2020-02-28
Doribax	Powder, for solution	250 mg/10mL	Intravenous	Janssen Pharmaceuticals	2010-10-15	2014-07-30
Doribax	Powder, for solution	500 mg / vial	Intravenous	Janssen Pharmaceuticals	2009-10-19	2013-07-03
Doribax	Powder, for solution	500 mg/10mL	Intravenous	Janssen Pharmaceuticals	2007-10-12	2014-07-30
Doribax	Injection, powder, for solution	250 mg	Intravenous	Janssen Cilag International Nv	2016-09-08	2014-10-17
Doripenem	Powder, for solution	250 mg/10mL	Intravenous	Apotex Corp.	2016-12-05	2019-07-31
Doripenem	Powder, for solution	500 mg/10mL	Intravenous	Apotex Corp.	2016-12-05	2019-08-31

Chemical Identifiers

UNII: BHV525JOBH
CAS number: 148016-81-3
InChI Key: AVAACINZEOAHHE-VFZPANTDSA-N
InChI: InChI=1S/C15H24N4O6S2/c1-6-11-10(7(2)20)14(21)19(11)12(15(22)23)13(6)26-9-3-8(17-5-9)4-18-27(16,24)25/h6-11,17-18,20H,3-5H2,1-2H3,(H,22,23)(H2,16,24,25)/t6-,7-,8+,9+,10-,11-/m1/s1
IUPAC Name: (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-{[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
SMILES: [H][C@]12[C@@H](C)C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)=C(N1C(=O)[C@]2([H])[C@@H](C)O)C(O)=O

References

General References

Jones RN, Huynh HK, Biedenbach DJ: Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrob Agents Chemother. 2004 Aug;48(8):3136-40. [Article]
Chahine EB, Ferrill MJ, Poulakos MN: Doripenem: a new carbapenem antibiotic. Am J Health Syst Pharm. 2010 Dec 1;67(23):2015-24. doi: 10.2146/ajhp090672. [Article]
Dedhia HV, McKnight R: Doripenem: position in clinical practice. Expert Rev Anti Infect Ther. 2009 Jun;7(5):507-14. doi: 10.1586/eri.09.37. [Article]
Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]

External Links

Human Metabolome Database: HMDB0041883
KEGG Drug: D03895
PubChem Compound: 73303
PubChem Substance: 310264862
ChemSpider: 66040
BindingDB: 50088382
RxNav: 119771
ChEBI: 135928
ChEMBL: CHEMBL491571
ZINC: ZINC000003922770
PDBe Ligand: O6P
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Doripenem

PDB Entries

6p9c

FDA label

Download (868 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Not Available	Healthy Subjects (HS)	1
4	Completed	Not Available	Ventilator Associated Bacterial Pneumonia (VABP)	1
4	Completed	Treatment	Bacterial Infections / Cross Infection / Infection / Intraabdominal Infections / Urinary Tract Infection / Ventilator Associated Bacterial Pneumonia (VABP)	1
4	Completed	Treatment	Febrile Neutropenia	1
4	Completed	Treatment	Pneumonia / Urinary Tract Infection / Ventilator Associated Bacterial Pneumonia (VABP)	1
4	Completed	Treatment	Sepsis	1
3	Completed	Treatment	Appendicitis / Bacterial Infections and Mycoses / Gallbladder Inflammation / Pancreatitis / Peritonitis	2
3	Completed	Treatment	Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis	2
3	Completed	Treatment	Pneumonia	1
3	Completed	Treatment	Pneumonia / Ventilators, Mechanical	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous
Injection, powder, lyophilized, for solution	Intravenous	500 mg
Injection, powder, for solution	Intravenous	250 mg
Powder, for solution	Intravenous
Powder, for solution	Intravenous	250 mg/10mL
Powder, for solution	Intravenous	500 mg/10mL
Powder, for solution	Intravenous	500 mg / vial
Injection, powder, lyophilized, for suspension	Intravenous	500 mg
Injection, powder, for solution	Intravenous	500 mg/1vial
Injection, powder, lyophilized, for solution	Intravenous	0.5 g
Injection, powder, for solution	Intravenous	500 mg
Powder		500 mg/1vial

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US5317016	No	1994-05-31	2012-08-14
CA2404703	No	2007-06-05	2021-03-30
CA2076430	No	1997-12-23	2012-08-19
US8247402	No	2012-08-21	2021-03-30

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	3.13 mg/mL	ALOGPS
logP	-1.3	ALOGPS
logP	-5.6	Chemaxon
logS	-2.1	ALOGPS
pKa (Strongest Acidic)	3.34	Chemaxon
pKa (Strongest Basic)	9.51	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	5	Chemaxon
Polar Surface Area	162.06 Å²	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	99.88 m³·mol^-1	Chemaxon
Polarizability	42.37 Å³	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	-	0.6542
Blood Brain Barrier	-	0.9633
Caco-2 permeable	-	0.6508
P-glycoprotein substrate	Substrate	0.7634
P-glycoprotein inhibitor I	Non-inhibitor	0.8733
P-glycoprotein inhibitor II	Non-inhibitor	1.0
Renal organic cation transporter	Non-inhibitor	0.9288
CYP450 2C9 substrate	Non-substrate	0.7918
CYP450 2D6 substrate	Non-substrate	0.8135
CYP450 3A4 substrate	Non-substrate	0.6002
CYP450 1A2 substrate	Non-inhibitor	0.8052
CYP450 2C9 inhibitor	Non-inhibitor	0.7661
CYP450 2D6 inhibitor	Non-inhibitor	0.8798
CYP450 2C19 inhibitor	Non-inhibitor	0.7305
CYP450 3A4 inhibitor	Non-inhibitor	0.9118
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9886
Ames test	Non AMES toxic	0.6139
Carcinogenicity	Non-carcinogens	0.6727
Biodegradation	Not ready biodegradable	0.8469
Rat acute toxicity	2.4823 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9799
hERG inhibition (predictor II)	Non-inhibitor	0.878

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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insights and accelerate drug research.

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Details1. Penicillin-binding protein 1A

Kind: Protein
Organism: Escherichia coli (strain K12)
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function: Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...
Gene Name: mrcA
Uniprot ID: P02918
Uniprot Name: Penicillin-binding protein 1A
Molecular Weight: 93635.545 Da

References

Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]

Details2. Penicillin-binding protein 1B

Kind: Protein
Organism: Escherichia coli (strain K12)
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function: Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...
Gene Name: mrcB
Uniprot ID: P02919
Uniprot Name: Penicillin-binding protein 1B
Molecular Weight: 94291.875 Da

References

Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]

Details3. Penicillin-binding protein 2

Kind: Protein
Organism: Escherichia coli (strain K12)
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function: Cell wall formation; PBP-2 is responsible for the determination of the rod shape of the cell. It synthesizes cross-linked peptidoglycan from lipid intermediates.
Gene Name: mrdA
Uniprot ID: P0AD65
Uniprot Name: Penicillin-binding protein 2
Molecular Weight: 70856.1 Da

References

Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]

Details4. Penicillin-binding protein 3

Kind: Protein
Organism: Pseudomonas aeruginosa
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Peptidoglycan glycosyltransferase activity
Specific Function: Not Available
Gene Name: pbpB
Uniprot ID: Q51504
Uniprot Name: Cell division protein
Molecular Weight: 62855.78 Da

References

Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]

Details5. Penicillin-binding protein 4

Kind: Protein
Organism: Staphylococcus aureus
Pharmacological action: Yes
Actions: Antagonist
Inhibitor

General Function: Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function: Not Available
Gene Name: pbp4
Uniprot ID: P72355
Uniprot Name: Penicillin-binding protein 4
Molecular Weight: 48237.14 Da

References

Dedhia HV, McKnight R: Doripenem: position in clinical practice. Expert Rev Anti Infect Ther. 2009 Jun;7(5):507-14. doi: 10.1586/eri.09.37. [Article]

Enzymes

Details1. Dipeptidase 1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Zinc ion binding
Specific Function: Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulati...
Gene Name: DPEP1
Uniprot ID: P16444
Uniprot Name: Dipeptidase 1
Molecular Weight: 45673.48 Da

References

Cirillo I, Mannens G, Janssen C, Vermeir M, Cuyckens F, Desai-Krieger D, Vaccaro N, Kao LM, Devineni D, Redman R, Turner K: Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men. Antimicrob Agents Chemother. 2008 Oct;52(10):3478-83. doi: 10.1128/AAC.00424-08. Epub 2008 Jul 21. [Article]

Transporters

Details1. Solute carrier family 22 member 8

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name: SLC22A8
Uniprot ID: Q8TCC7
Uniprot Name: Solute carrier family 22 member 8
Molecular Weight: 59855.585 Da

References

Greer ND: Doripenem (Doribax): the newest addition to the carbapenems. Proc (Bayl Univ Med Cent). 2008 Jul;21(3):337-41. [Article]

Drug created at March 19, 2008 16:17 / Updated at February 21, 2021 18:52

Doripenem

Identification

Structure for Doripenem (DB06211)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

References

References

References

References

Enzymes

References

Transporters

References