Identification

Summary

Maribavir is a cytomegalovirus (CMV) pUL97 kinase inhibitor used for the treatment of refractory post-transplant CMV infection.

Generic Name
Maribavir
DrugBank Accession Number
DB06234
Background

Maribavir is an inhibitor of the cytomegalovirus (CMV; HHV5) pUL97 kinase which is used to treat CMV infections in patients post-transplantation.5 Most standard CMV therapies, such as ganciclovir or foscarnet, target CMV DNA polymerase - while generally effective, these medications tend to promote the development of CMV resistance to DNA polymerase-based therapies, and their use is often limited by toxicities like myelosuppression and renal injury.4 Maribavir is novel in that it instead targets the CMV pUL97 kinase, thereby providing an effective alternative treatment option in cases of resistant infections.

Maribavir was approved by the FDA in November 2021, under the name Livtencity (Takeda), for the treatment of resistant CMV infections in post-transplant patients.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 376.23
Monoisotopic: 375.0752615
Chemical Formula
C15H19Cl2N3O4
Synonyms
  • Maribavir
External IDs
  • 1263-W-94
  • 1263W94

Pharmacology

Indication

Maribavir is indicated for the treatment of adult and pediatric patients (weighing >35kg and at least 12 years old) with post-transplant cytomegalovirus (CMV) infection which is refractory to standard treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet.5

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Maribavir exerts its antiviral efficacy via an alternative target as compared to traditional CMV antivirals and is thus useful in the treatment of CMV infections that have proven resistant to standard therapy.6

Maribavir should not be used concomitantly with ganciclovir or valganciclovir, as these molecules both require activation via CMV pUL97 in order to exert their antiviral effect. Taking them alongside maribavir - an inhibitor of this same kinase - will therefore significantly reduce their antiviral activity.5

Mechanism of action

Human cytomegalovirus (CMV) is a herpesvirus commonly causing infection in patients following stem cell or organ transplants.6 As with other herpesviruses, CMV tends to persist in the host and become reactivated under immunosuppressive conditions3 - patients requiring multiple immunosuppressive medications to combat transplant rejection are thus at a much higher risk of developing serious CMV infections.3,6

Maribavir belongs to a class of anti-cytomegalovirus antivirals called benzimidazole ribosides.3 It competitively inhibits the human CMV pUL97 viral protein kinase, which results in viable but severely defective viruses upon replication,4 although the reasons for this remain poorly defined. In addition, maribavir also inhibits viral release from the nucleus to the cytoplasm by inhibiting pUL97-dependent phosphorylation of the nuclear lamina component lamin A/C, although the extent to which this activity contributes to its antiviral efficacy is unclear.4

TargetActionsOrganism
ASerine/threonine protein kinase UL97
inhibitor
HHV-5
Absorption

Population pharmacokinetic modeling in patients receiving maribavir 400mg twice daily showed an AUC0-tau and Cmax of 128 µg.h/mL and 17.2 µg/mL, respectively.5 It has a median Tmax of one to three hours.5

Volume of distribution

The mean apparent steady-state volume of distribution for maribavir was 27.3 L.5

Protein binding

Across all concentration ranges tested, maribavir was extensively (~98%) protein-bound in plasma,5 likely primarily to serum albumin and alpha-1-acid glycoprotein.3

Metabolism

Maribavir is extensively metabolized following oral administration, primarily by CYP3A4 and, to a lesser extent, by CYP1A2.5 Its major circulating metabolite is VP 44469, an inactive N-dealkylated metabolite.5

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Route of elimination

Maribavir is eliminated primarily via hepatic metabolism.5 Following the oral administration of radiolabeled maribavir, 61% of the dose was excreted in the urine (<2% as unchanged drug) and 14% was excreted in the feces (5.7% as unchanged drug).5

Half-life

In post-transplant patients, the mean half-life of elimination was 4.32 hours.5

Clearance

In post-transplant patients, the mean oral clearance of maribavir was 2.85 L/h.5

Adverse Effects
Adverseeffects
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Toxicity

Data are limited regarding overdosage with maribavir. As there is no specific antidote for maribavir overdose, patients suspected of overdosage should be monitored closely for adverse reactions and treated symptomatically as clinically indicated.5 As maribavir is extensively protein-bound in plasma, dialysis is unlikely to be of benefit.5

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.
DrugInteraction
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Maribavir.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Maribavir.
ApalutamideThe serum concentration of Maribavir can be decreased when it is combined with Apalutamide.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Maribavir.
Bacillus calmette-guerin substrain russian BCG-I live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Maribavir.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Maribavir.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Maribavir.
CarbamazepineThe serum concentration of Maribavir can be decreased when it is combined with Carbamazepine.
CyclosporineThe serum concentration of Cyclosporine can be increased when it is combined with Maribavir.
DexamethasoneThe serum concentration of Maribavir can be decreased when it is combined with Dexamethasone.
Interactions
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Food Interactions
  • Avoid St. John's Wort. Co-administration with St. John's wort decreases serum levels of maribavir and may decrease its therapeutic efficacy.
  • Take with or without food. The co-administration of food with maribavir does not significantly affect its disposition.

Products

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International/Other Brands
Camvia (ViroPharma Inc.) / Livtencity (Takeda Pharmaceuticals America, Inc.)

Categories

ATC Codes
J05AX10 — Maribavir
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzimidazole ribonucleosides and ribonucleotides. These are nucleosides with a structure that consists of an imidazole moiety of benzimidazole is N-linked to a ribose (or deoxyribose). Nucleotides have a phosphate group linked to the C5 carbon of the ribose (or deoxyribose) moiety.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Benzimidazole ribonucleosides and ribonucleotides
Sub Class
Not Available
Direct Parent
Benzimidazole ribonucleosides and ribonucleotides
Alternative Parents
Glycosylamines / Pentoses / Benzimidazoles / Secondary alkylarylamines / N-substituted imidazoles / Aminoimidazoles / Benzenoids / Aryl chlorides / Heteroaromatic compounds / Tetrahydrofurans
show 7 more
Substituents
1-ribofuranosylbenzimidazole / Alcohol / Amine / Aminoimidazole / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • HHV-5

Chemical Identifiers

UNII
PTB4X93HE1
CAS number
176161-24-3
InChI Key
KJFBVJALEQWJBS-XUXIUFHCSA-N
InChI
InChI=1S/C15H19Cl2N3O4/c1-6(2)18-15-19-9-3-7(16)8(17)4-10(9)20(15)14-13(23)12(22)11(5-21)24-14/h3-4,6,11-14,21-23H,5H2,1-2H3,(H,18,19)/t11-,12-,13-,14-/m0/s1
IUPAC Name
(2S,3S,4R,5S)-2-{5,6-dichloro-2-[(propan-2-yl)amino]-1H-1,3-benzodiazol-1-yl}-5-(hydroxymethyl)oxolane-3,4-diol
SMILES
CC(C)NC1=NC2=CC(Cl)=C(Cl)C=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O

References

Synthesis Reference

Glover BN, Huang LF, Lancaster RW, Long ST, Rizzolio MC, Schmitt EA, Sickles BR. (2010). Crystalline forms of an antiviral benzimidazole compound (US Patent No. US7714123B2).

General References
  1. Sun K, Welty D: Elucidation of Metabolic and Disposition Pathways for Maribavir in Nonhuman Primates through Mass Balance and Semi-Physiologically Based Modeling Approaches. Drug Metab Dispos. 2021 Nov;49(11):1025-1037. doi: 10.1124/dmd.121.000493. Epub 2021 Aug 30. [Article]
  2. Goldwater DR, Dougherty C, Schumacher M, Villano SA: Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults. Antimicrob Agents Chemother. 2008 May;52(5):1794-8. doi: 10.1128/AAC.00951-07. Epub 2008 Mar 3. [Article]
  3. Koszalka GW, Johnson NW, Good SS, Boyd L, Chamberlain SC, Townsend LB, Drach JC, Biron KK: Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 2002 Aug;46(8):2373-80. doi: 10.1128/AAC.46.8.2373-2380.2002. [Article]
  4. Hakki M: Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy. Curr Hematol Malig Rep. 2020 Apr;15(2):90-102. doi: 10.1007/s11899-020-00557-6. [Article]
  5. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]
  6. FDA News Release: FDA Approves First Treatment for Common Type of Post-Transplant Infection that is Resistant to Other Drugs [Link]
ChemSpider
413807
ChEMBL
CHEMBL515408
ZINC
ZINC000003824412
Wikipedia
Maribavir

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedPreventionCytomegalovirus (CMV) Infection2
3CompletedTreatmentCytomegalovirus (CMV)1
3RecruitingTreatmentCytomegalovirus (CMV)1
2CompletedPreventionCytomegalovirus (CMV) Infection1
2CompletedTreatmentCytomegalovirus (CMV)1
1CompletedBasic ScienceCytomegalovirus (CMV)1
1CompletedTreatmentCytomegalovirus (CMV) Infection / Human Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHealthy Subjects (HS)1
1TerminatedTreatmentHealthy Subjects (HS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.72 mg/mLALOGPS
logP2.15ALOGPS
logP1.84ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)12.45ChemAxon
pKa (Strongest Basic)6.38ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area99.77 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity90.01 m3·mol-1ChemAxon
Polarizability37.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Targets

Drugtargets2
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Kind
Protein
Organism
HHV-5
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein kinase activity
Specific Function
Serine/threonine protein kinase that plays important roles in several processes including nuclear viral egress, viral replication or regulation of host cell cycle progression. Participates in the a...
Gene Name
UL97
Uniprot ID
P16788
Uniprot Name
Serine/threonine protein kinase UL97
Molecular Weight
78231.9 Da
References
  1. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Koszalka GW, Johnson NW, Good SS, Boyd L, Chamberlain SC, Townsend LB, Drach JC, Biron KK: Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 2002 Aug;46(8):2373-80. doi: 10.1128/AAC.46.8.2373-2380.2002. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Koszalka GW, Johnson NW, Good SS, Boyd L, Chamberlain SC, Townsend LB, Drach JC, Biron KK: Preclinical and toxicology studies of 1263W94, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 2002 Aug;46(8):2373-80. doi: 10.1128/AAC.46.8.2373-2380.2002. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Livtencity (maribavir) tablets for oral use [Link]

Drug created at March 19, 2008 16:18 / Updated at November 30, 2021 07:50