Identification

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Name
Doravirine
Accession Number
DB12301
Type
Small Molecule
Groups
Approved, Investigational
Description

Doravirine has been used in trials studying the treatment of HIV-1, HIV-1 Infection, Renal Impairment, and Human Immunodeficiency Virus (HIV) Infection.

In particular, doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) intended to be administered in combination with other antiretroviral medicines Label,4. Doravirine is subsequently 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 managing HIV-1 infection or AIDS 4.

Structure
Thumb
Synonyms
  • Doravirine
External IDs
MK-1439
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PifeltroTablet100 mgOralMerck Ltd.2018-11-14Not applicableCanada
PifeltroTablet, film coated100 mg/1OralMerck Sharp & Dohme Corp.2018-07-20Not applicableUs
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 End
DelstrigoDoravirine (100 mg) + Lamivudine (300 mg) + Tenofovir disoproxil fumarate (300 mg)TabletOralMerck Ltd.2018-12-10Not applicableCanada
DelstrigoDoravirine (100 mg/1) + Lamivudine (300 mg/1) + Tenofovir disoproxil fumarate (300 mg/1)Tablet, film coatedOralMerck Sharp & Dohme Corp.2018-07-20Not applicableUs
Categories
UNII
913P6LK81M
CAS number
1338225-97-0
Weight
Average: 425.749
Monoisotopic: 425.050251565
Chemical Formula
C17H11ClF3N5O3
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-[(5-hydroxy-4-methyl-4H-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

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 Label.

Pharmacodynamics

In a clinical Phase 2 trial evaluating over a dose range of 0.25 to 2 times 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 Label.

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 Label.

Mechanism of action

Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 Label,1,2. As reverse transcriptase is the principal virally encoded enzyme with which retroviruses like HIV convert their RNA genomes into DNA for the purposes of proliferation within the host genome of infected cells 3, doravirine subsequently functions by inhibiting HIV-1 replication by the non-competitive inhibition of HIV-1 reverse transcriptase (RT) Label. Doravirine does not however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ Label.

TargetActionsOrganism
UReverse transcriptase/RNaseH
inhibitor
Human immunodeficiency virus 1
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

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Absorption

The absolute bioavailability of doravirine is reported to be 64% with a Tmax of 2 hours Label. Following oral [14 C]doravirine administration, all of the administered dose was recovered 1 and the agent is considered to be well absorbed 2. Moreover, the co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies 2.

Volume of distribution

The Vdss documented for doravirine is 60.5 L, based on an IV dosing Label.

Protein binding

The plasma protein binding recorded for doravirine is 76% Label.

Metabolism

Once administered and absorbed into the plasma circulation, unchanged doravirine is the major circulating component, followed by its M9 metabolite - a product of cytochrome P450 3A4/5 mediated oxidative metabolism, resulting in the addition of oxygen to doravirine's triazolone ring - as the most abundant doravirine metabolite present 1.

Route of elimination

The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism Label,1,2. Only 6% of administered doses are found in the urine, unchanged Label. Minor levels of the drug are found in the biliary/fecal elimination routes, unchanged Label.

Half life

The elimination half-life t1/2 determined for doravirine is recorded as 15 hours Label.

Clearance

The elimination clearance values CL/F and CLrenal have been determined as 106 (35.2) ml/min and 9.3 (18.6) ml/min, presented as geometric means (%CV: geometric coefficient of variation) Label.

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 Label.

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

It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant Label. 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 Label.

Safety and efficacy of PIFELTRO have not been established in pediatric patients less than 18 years of age Label.

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 concomitant disease or other drug therapy Label.

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 Label.

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) Label.

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 Label. 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 Label.

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 Label.

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 Label.

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
(R)-warfarinThe metabolism of Doravirine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Doravirine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Doravirine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Doravirine.
5-androstenedioneThe metabolism of Doravirine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Doravirine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Doravirine can be decreased when combined with 6-O-benzylguanine.
7-ethyl-10-hydroxycamptothecinThe metabolism of Doravirine can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Doravirine.
AbataceptThe metabolism of Doravirine can be increased when combined with Abatacept.
Additional Data Available
  • Extended Description
    Extended Description

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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

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  • Action
    Action

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Food Interactions
Not Available

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]
External Links
PubChem Compound
58460047
PubChem Substance
347828567
ChemSpider
28424197
ChEMBL
CHEMBL2364608
HET
2KW
Wikipedia
Doravirine
ATC Codes
J05AR24 — Lamivudine, tenofovir disoproxil and doravirineJ05AG06 — Doravirine
AHFS Codes
  • 08:18.08.16 — Nonnucleoside Reverse Transcriptase Inhibitors
PDB Entries
4ncg
FDA label
Download (263 KB)
MSDS
Download (98.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherHuman Immunodeficiency Virus (HIV)1
1CompletedTreatmentDrug Interaction Potentiation / Human Immunodeficiency Virus (HIV) / Late phase Tuberculosis / Rifamycins Causing Adverse Effects in Therapeutic Use1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
1CompletedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection2
1CompletedTreatmentImpaired Renal Function1
1, 2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2Not Yet RecruitingTreatmentHIV-1-infection1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
3Active Not RecruitingTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
3Not Yet RecruitingTreatmentHIV-1-infection1

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)
US8486975No2013-07-162031-10-07Us
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
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0115 mg/mLALOGPS
logP3.47ALOGPS
logP2.19ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)7.34ChemAxon
pKa (Strongest Basic)1.12ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area104.27 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity98.37 m3·mol-1ChemAxon
Polarizability35.42 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

Taxonomy

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
Diaryl ether / Benzonitrile / Phenoxy compound / Phenol ether / Chlorobenzene / Dihydropyridine / Halobenzene / Pyridinone / Aryl chloride / Aryl halide
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not 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

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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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]

Drug created on October 20, 2016 15:52 / Updated on October 22, 2019 18:27