Identification

Name
Doravirine
Accession Number
DB12301
Description

Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) intended to be administered in combination with other antiretroviral medicines.5,4 Doravirine is available by itself or as a combination product of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg).4

Doravirine is formally indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, further expanding the possibility and choice of therapeutic treatments available for the management of HIV-1 infection.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 425.749
Monoisotopic: 425.050251565
Chemical Formula
C17H11ClF3N5O3
Synonyms
  • Doravirine
  • Doravirinum
External IDs
  • MK 1439
  • MK-1439

Pharmacology

Indication

Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history.5 It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.5

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

In a clinical phase 2 trial evaluating a dose range of 0.25-2x the recommended dose of doravirine (in combination with emtricitabine/tenofovir) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.5

Furthermore, at a dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose, doravirine does not prolong the QT interval to any clinically relevant extent.5

Mechanism of action

Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1.5,1,2 Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome - this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication.3 Doravirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase.5 Doravirine does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.5

TargetActionsOrganism
UReverse transcriptase/RNaseH
inhibitor
Human immunodeficiency virus 1
Absorption

The absolute bioavailability of doravirine is 64% with a Tmax of 2 hours.5 Following oral [14C]doravirine administration, all of the administered dose was recovered1 and the agent is considered to be well absorbed.2 Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies.2

Volume of distribution

The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L.5

Protein binding

Doravirine is approximately 76% protein-bound in plasma.5

Metabolism

Following absorption, unchanged parent drug is the major circulating component in plasma. Its M9 metabolite - a product of cytochrome P450 3A4/5 mediated oxidative metabolism - is the most abundant doravirine metabolite in the circulation.1

Hover over products below to view reaction partners

Route of elimination

The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism.5,1,2 Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces.5

Half-life

The elimination half-life determined of doravirine is 15 hours.5

Clearance

The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively.5

Adverse Effects
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Toxicity

No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown.5

No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes.5

It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant.5 Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine.5

The safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age.5

Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidities or other drug therapy.5

No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients.5

No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).5

Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD.5 A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls.5

Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.5

There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD.5

Affected organisms
  • Humans and other mammals
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
AbametapirThe serum concentration of Doravirine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Doravirine can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Doravirine can be decreased when combined with Acalabrutinib.
AdalimumabThe metabolism of Doravirine can be increased when combined with Adalimumab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Doravirine.
AlfentanilThe metabolism of Doravirine can be decreased when combined with Alfentanil.
AlprazolamThe metabolism of Doravirine can be decreased when combined with Alprazolam.
AmbrisentanThe metabolism of Doravirine can be decreased when combined with Ambrisentan.
AmitriptylineThe metabolism of Doravirine can be decreased when combined with Amitriptyline.
AmprenavirThe metabolism of Doravirine can be decreased when combined with Amprenavir.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of doravirine and may reduce its serum concentration. Co-administration of doravirine with St. John's Wort is contraindicated.
  • Take at the same time every day.
  • Take with or without food. Co-administration with food slightly alters pharmacokinetics, but not to a clinically significant extent.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PifeltroTablet, film coated100 mg/1OralMerck Sharp & Dohme Corp.2018-07-20Not applicableUS flag
PifeltroTablet100 mgOralMerck Ltd.2018-11-14Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
DelstrigoDoravirine (100 mg/1) + Lamivudine (300 mg/1) + Tenofovir disoproxil fumarate (300 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Corp.2018-07-20Not applicableUS flag
DelstrigoDoravirine (100 mg) + Lamivudine (300 mg) + Tenofovir disoproxil fumarate (300 mg)TabletOralMerck Ltd.2018-12-10Not applicableCanada flag

Categories

ATC Codes
J05AR24 — Lamivudine, tenofovir disoproxil and doravirineJ05AG06 — Doravirine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Phenoxy compounds / Phenol ethers / Benzonitriles / Pyridinones / Chlorobenzenes / Dihydropyridines / Aryl chlorides / Triazoles / Heteroaromatic compounds / Lactams
show 7 more
Substituents
1,2,4-triazole / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid / Benzonitrile
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
913P6LK81M
CAS number
1338225-97-0
InChI Key
ZIAOVIPSKUPPQW-UHFFFAOYSA-N
InChI
InChI=1S/C17H11ClF3N5O3/c1-25-13(23-24-16(25)28)8-26-3-2-12(17(19,20)21)14(15(26)27)29-11-5-9(7-22)4-10(18)6-11/h2-6H,8H2,1H3,(H,24,28)
IUPAC Name
3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile
SMILES
CN1C(=O)NN=C1CN1C=CC(=C(OC2=CC(=CC(Cl)=C2)C#N)C1=O)C(F)(F)F

References

General References
  1. Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B, Tatavarti A, Liu R, Anderson MS, Behm MO, Fan L, Li Y, Butterton JR, Iwamoto M, Khalilieh SG: Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica. 2018 Mar 28:1-11. doi: 10.1080/00498254.2018.1451667. [PubMed:29557716]
  2. Wilby KJ, Eissa NA: Clinical Pharmacokinetics and Drug Interactions of Doravirine. Eur J Drug Metab Pharmacokinet. 2018 Jul 25. pii: 10.1007/s13318-018-0497-3. doi: 10.1007/s13318-018-0497-3. [PubMed:30047107]
  3. Hu WS, Hughes SH: HIV-1 reverse transcription. Cold Spring Harb Perspect Med. 2012 Oct 1;2(10). pii: cshperspect.a006882. doi: 10.1101/cshperspect.a006882. [PubMed:23028129]
  4. Merck Pifeltro FDA Approval Press Release [Link]
  5. FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]
PubChem Compound
58460047
PubChem Substance
347828567
ChemSpider
28424197
RxNav
2055755
ChEMBL
CHEMBL2364608
ZINC
ZINC000072317283
PDBe Ligand
2KW
Wikipedia
Doravirine
AHFS Codes
  • 08:18.08.16 — Nonnucleoside Reverse Transcriptase Inhibitors
PDB Entries
4ncg
FDA label
Download (263 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
4Not Yet RecruitingPreventionHuman Immunodeficiency Virus (HIV) Infections1
4Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
4Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
3Not Yet RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection3
3RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection2
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
TabletOral100 mg
Tablet, film coatedOral100 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8486975No2013-07-162031-10-07US flag
US10603282No2016-11-292036-11-29US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00321 mg/mLALOGPS
logP3.51ALOGPS
logP2.23ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)9.66ChemAxon
pKa (Strongest Basic)-2.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area98.03 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity96.41 m3·mol-1ChemAxon
Polarizability36.06 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

Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72547
Uniprot Name
Reverse transcriptase/RNaseH
Molecular Weight
65223.615 Da
References
  1. FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B, Tatavarti A, Liu R, Anderson MS, Behm MO, Fan L, Li Y, Butterton JR, Iwamoto M, Khalilieh SG: Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica. 2018 Mar 28:1-11. doi: 10.1080/00498254.2018.1451667. [PubMed:29557716]
  2. Yee KL, Sanchez RI, Auger P, Liu R, Fan L, Triantafyllou I, Lai MT, Di Spirito M, Iwamoto M, Khalilieh SG: Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects. Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: AAC.01757-16. doi: 10.1128/AAC.01757-16. Print 2017 Feb. [PubMed:27872069]
  3. FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Sanchez RI, Fillgrove KL, Yee KL, Liang Y, Lu B, Tatavarti A, Liu R, Anderson MS, Behm MO, Fan L, Li Y, Butterton JR, Iwamoto M, Khalilieh SG: Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans. Xenobiotica. 2018 Mar 28:1-11. doi: 10.1080/00498254.2018.1451667. [PubMed:29557716]
  2. FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]

Drug created on October 20, 2016 15:52 / Updated on September 20, 2020 08:49

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