Identification

Name
Doripenem
Accession Number
DB06211
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
Not Available
External IDs
S-4661
Product Ingredients
IngredientUNIICASInChI Key
doripenem hydrate4B035T6NKT364622-82-2NTUBEBXBDGKBTJ-WGLOMNHJSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DoribaxPowder, for solution500 mgIntravenousJanssen Pharmaceuticals2009-10-192013-07-03Canada
DoribaxPowder, for solution250 mg/10mLIntravenousShionogi2010-10-15Not applicableUs
DoribaxPowder, for solution500 mg/10mLIntravenousShionogi2007-10-12Not applicableUs
DoripenemPowder, for solution250 mg/10mLIntravenousApotex Corporation2016-12-05Not applicableUs
DoripenemPowder, for solution500 mg/10mLIntravenousApotex Corporation2016-12-05Not applicableUs
Unapproved/Other Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DoribaxInjection, powder, for solution500 mgIntravenousJanssen Cilag International Nv2008-07-25Not applicableEu
DoribaxInjection, powder, for solution250 mgIntravenousJanssen Cilag International Nv2008-07-25Not applicableEu
International/Other Brands
Finibax (Shionogi Co.)
Categories
UNII
BHV525JOBH
CAS number
Not Available
Weight
Average: 420.504
Monoisotopic: 420.1137259
Chemical Formula
C15H24N4O6S2
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][[email protected]]12[[email protected]@H](C)C(S[[email protected]]3([H])CN[[email protected]](CNS(N)(=O)=O)C3)=C(N1C(=O)[[email protected]]2([H])[[email protected]@H](C)O)C(O)=O

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.

Structured Indications
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.

TargetActionsOrganism
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.

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.

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.

Affected organisms
  • Various aerobic and anaerobic microorganisms
  • Pseudomonas aeruginosa
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Escherichia coli
  • Staphylococcus aureus
  • Enterococcus faecalis
  • Moraxella catarrhalis
  • Acinetobacter
  • Enterococcus faecium
  • Klebsiella
  • Enterobacter
  • Streptococcus constellatus
  • Proteus mirabilis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
ProbenecidThe serum concentration of Doripenem can be increased when it is combined with Probenecid.Approved
Valproic AcidThe serum concentration of Valproic Acid can be decreased when it is combined with Doripenem.Approved, Investigational
Food Interactions
No interactions found.

References

General References
  1. 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. [PubMed:15273134]
  2. 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. [PubMed:21098373]
  3. 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. [PubMed:19485791]
  4. 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. [PubMed:19243706]
External Links
Human Metabolome Database
HMDB41883
KEGG Drug
D03895
PubChem Compound
73303
PubChem Substance
310264862
ChemSpider
66040
ChEBI
135928
ChEMBL
CHEMBL491571
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Doripenem
ATC Codes
J01DH04 — Doripenem
FDA label
Download (868 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableInfections, Bacterial1
1CompletedHealth Services ResearchHealthy Volunteers1
1TerminatedNot AvailableMeningitis1
2CompletedTreatmentAbdominal Abscess / Infections, Bacterial / Pneumonia / Pneumonia, Bacterial / Ventilator-Associated Pneumonia (VAP)1
2CompletedTreatmentHospital Acquired Infections / Pneumonia / Pneumonia, Bacterial / Ventilator-Associated Pneumonia (VAP)1
2CompletedTreatmentUrinary Tract Infections (UTIs)1
3CompletedTreatmentAppendicitis / Bacterial Infections and Mycoses / Gallbladder Inflammation / Pancreatitis / Peritonitis2
3CompletedTreatmentComplicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis2
3CompletedTreatmentPneumonia1
3CompletedTreatmentPneumonia / Ventilators, Mechanical1
3CompletedTreatmentPyelonephritis / Urinary Tract Infections (UTIs)1
3TerminatedTreatmentAbdominal Abscess / Abdominal Pain (AP) / Abscess, Intra-Abdominal / Acute Abdomen / Appendicitis / Ileus / Infection NOS / Intestinal Perforations / Peritonitis / Rupture1
3TerminatedTreatmentCommunity-Acquired Infections / Hospital Acquired Infections / Pneumonia, Bacterial / Ventilator-Associated Pneumonia (VAP)1
3TerminatedTreatmentComplicated Urinary Tract Infections or Pyelonephritis1
3TerminatedTreatmentVentilator-Associated Pneumonia (VAP)1
4CompletedNot AvailableHealthy Volunteers1
4CompletedNot AvailableHospital Acquired Infections / Intraabdominal Infections / Pneumonia, Bacterial / Urinary Tract Infections (UTIs)1
4CompletedNot AvailableVentilator-Associated Pneumonia (VAP)1
4CompletedTreatmentCross Infection / Infection NOS / Infections, Bacterial / Intra-Abdominal Infections / Urinary Tract Infections (UTIs) / Ventilator-Associated Pneumonia (VAP)1
4CompletedTreatmentNeutropenia, Febrile1
4CompletedTreatmentPneumonia / Urinary Tract Infections (UTIs) / Ventilator-Associated Pneumonia (VAP)1
4CompletedTreatmentSepsis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous250 mg
Injection, powder, for solutionIntravenous500 mg
Powder, for solutionIntravenous250 mg/10mL
Powder, for solutionIntravenous500 mg
Powder, for solutionIntravenous500 mg/10mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5317016No1992-08-142012-08-14Us
CA2404703No2007-06-052021-03-30Canada
CA2076430No1997-12-232012-08-19Canada
US8247402No2001-03-302021-03-30Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility3.13 mg/mLALOGPS
logP-1.3ALOGPS
logP-5.6ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)3.54ChemAxon
pKa (Strongest Basic)9.51ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area162.06 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity99.88 m3·mol-1ChemAxon
Polarizability42.37 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6542
Blood Brain Barrier-0.9633
Caco-2 permeable-0.6508
P-glycoprotein substrateSubstrate0.7634
P-glycoprotein inhibitor INon-inhibitor0.8733
P-glycoprotein inhibitor IINon-inhibitor1.0
Renal organic cation transporterNon-inhibitor0.9288
CYP450 2C9 substrateNon-substrate0.7918
CYP450 2D6 substrateNon-substrate0.8135
CYP450 3A4 substrateNon-substrate0.6002
CYP450 1A2 substrateNon-inhibitor0.8052
CYP450 2C9 inhibitorNon-inhibitor0.7661
CYP450 2D6 inhibitorNon-inhibitor0.8798
CYP450 2C19 inhibitorNon-inhibitor0.7305
CYP450 3A4 inhibitorNon-inhibitor0.9118
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9886
Ames testNon AMES toxic0.6139
CarcinogenicityNon-carcinogens0.6727
BiodegradationNot ready biodegradable0.8469
Rat acute toxicity2.4823 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9799
hERG inhibition (predictor II)Non-inhibitor0.878
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as thienamycins. These are beta-lactam antibiotics that differ from penicillins in having the thiazolidine sulfur atom replaced by carbon, the sulfur then becoming the first atom in the side chain.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Lactams
Sub Class
Beta lactams
Direct Parent
Thienamycins
Alternative Parents
Alpha amino acids and derivatives / Pyrroline carboxylic acids / Azepines / Vinylogous thioesters / Sulfuric acid diamides / Tertiary carboxylic acid amides / Pyrrolidines / Thioenol ethers / Secondary alcohols / Amino acids
show 10 more
Substituents
Thienamycin / Alpha-amino acid or derivatives / Pyrroline carboxylic acid / Pyrroline carboxylic acid or derivatives / Azepine / Vinylogous thioester / Sulfuric acid diamide / Pyrroline / Pyrrolidine / Tertiary carboxylic acid amide
show 26 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

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
  1. 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. [PubMed:19243706]
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
  1. 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. [PubMed:19243706]
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
  1. 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. [PubMed:19243706]
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
  1. 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. [PubMed:19243706]
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
  1. 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. [PubMed:19485791]

Enzymes

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:18644951]

Drug created on March 19, 2008 10:17 / Updated on October 02, 2017 05:43