Identification
- Summary
Doravirine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals to treat HIV-1 infections.
- Brand Names
- Delstrigo, Pifeltro
- Generic Name
- Doravirine
- DrugBank Accession Number
- DB12301
- Background
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
Structure for Doravirine (DB12301)
- 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
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Human immunodeficiency virus type 1 (hiv-1) Combination Product in combination with: Lamivudine (DB00709), Tenofovir disoproxil (DB00300) •••••••••••• ••••• •••••• Used as adjunct in combination to treat Human immunodeficiency virus type 1 (hiv-1) •••••••••••• ••••• •• ••••••• •• ••••••••• •••••••• •• •••••••••• ••••••••••••••••••••• •••••••••• •••••••••••••••••••••••• •••••• Used as adjunct in combination to treat Human immunodeficiency virus type 1 (hiv-1) •••••••••••• ••••• •••••••••••••• ••••• •••••• Used in combination to treat Human immunodeficiency virus type 1 (hiv-1) infection •••••••••••• ••••• •••••••••• •• •••••••• •••• ••••••• •••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism UReverse transcriptase/RNaseH inhibitorHuman 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
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- 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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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
- 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 Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Doravirine can be increased when it is combined with Abametapir. Abatacept The metabolism of Doravirine can be increased when combined with Abatacept. Acalabrutinib The metabolism of Doravirine can be decreased when combined with Acalabrutinib. Adalimumab The metabolism of Doravirine can be increased when combined with Adalimumab. Adenovirus type 7 vaccine live The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Doravirine. - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Pifeltro Tablet, film coated 100 mg/1 Oral A-S Medication Solutions 2018-07-20 Not applicable US 
Pifeltro Tablet, film coated 100 mg/1 Oral A-S Medication Solutions 2018-07-20 Not applicable US Pifeltro Tablet, film coated 100 mg Oral Merck Sharp & Dohme B.V. 2021-01-12 Not applicable EU 
Pifeltro Tablet 100 mg Oral Merck Ltd. 2018-11-14 Not applicable Canada 
Pifeltro Tablet, film coated 100 mg Oral Merck Sharp & Dohme B.V. 2021-01-12 Not applicable EU - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Delstrigo Doravirine (100 mg) + Lamivudine (300 mg) + Tenofovir disoproxil fumarate (245 mg) Tablet, film coated Oral Merck Sharp & Dohme B.V. 2021-01-12 Not applicable EU DELSTRIGO Doravirine (100 MG) + Lamivudine (300 MG) + Tenofovir disoproxil (245 MG) Tablet, film coated Oral Merck Sharp & Dohme B.V. 2019-05-28 Not applicable Italy 
Delstrigo Doravirine (100 mg) + Lamivudine (300 mg) + Tenofovir disoproxil fumarate (245 mg) Tablet, film coated Oral Merck Sharp & Dohme B.V. 2021-01-12 Not applicable EU Delstrigo Doravirine (100 mg) + Lamivudine (300 mg) + Tenofovir disoproxil fumarate (300 mg) Tablet Oral Merck Ltd. 2018-12-10 Not applicable Canada DELSTRIGO Doravirine (100 MG) + Lamivudine (300 MG) + Tenofovir disoproxil (245 MG) Tablet, film coated Oral Merck Sharp & Dohme B.V. 2019-05-28 Not applicable Italy
Categories
- ATC Codes
- J05AR24 — Lamivudine, tenofovir disoproxil and doravirine
- J05AR — Antivirals for treatment of HIV infections, combinations
- J05A — DIRECT ACTING ANTIVIRALS
- J05 — ANTIVIRALS FOR SYSTEMIC USE
- J — ANTIINFECTIVES FOR SYSTEMIC USE
- Drug Categories
- Antiinfectives for Systemic Use
- Antiviral Agents
- Antivirals for Systemic Use
- Antivirals used in combination for the treatment of HIV infections
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Direct Acting Antivirals
- Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor
- Non-Nucleoside Reverse Transcriptase Inhibitors
- Nonnucleoside Reverse Transcriptase Inhibitors
- Pyridines
- 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
- Affected organisms
- Humans and other mammals
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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Merck Pifeltro FDA Approval Press Release [Link]
- FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]
- External Links
- PubChem Compound
- 58460047
- PubChem Substance
- 347828567
- ChemSpider
- 28424197
- 2055755
- ChEMBL
- CHEMBL2364608
- ZINC
- ZINC000072317283
- PDBe Ligand
- 2KW
- Wikipedia
- Doravirine
- PDB Entries
- 4ncg / 7z2g / 7z2h
- FDA label
- Download (263 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Human Immunodeficiency Virus Type 1 (HIV-1) Infection 1 4 Completed Other HIV-infected Participants With ESRD Undergoing Routine Hemodialysis 1 4 Completed Treatment Human Immunodeficiency Virus Type 1 (HIV-1) Infection 1 4 Enrolling by Invitation Treatment Drug Drug Interaction (DDI) / Drug Resistance / Human Immunodeficiency Virus (HIV) Infections 1 4 Enrolling by Invitation Treatment Human Immunodeficiency Virus (HIV) Infections / Weight Gain 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, film coated Oral Tablet Oral 100 mg Tablet Oral 100.000 mg Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 100 MG Tablet, film coated Oral 100.0 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8486975 No 2013-07-16 2031-10-07 US US10603282 No 2020-03-31 2036-11-29 US US10842751 No 2020-11-24 2036-11-29 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00321 mg/mL ALOGPS logP 3.51 ALOGPS logP 2.23 Chemaxon logS -5.1 ALOGPS pKa (Strongest Acidic) 9.66 Chemaxon pKa (Strongest Basic) -2.6 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 98.03 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 96.41 m3·mol-1 Chemaxon Polarizability 36.06 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0000900000-293492696850033e26f9 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-0203900000-200d0bfa917225ca7e43 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-2904000000-4cd8f390bd41230c002e Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0209500000-a98e4786d273906ffa34 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001l-9003000000-47860f2f109aade51592 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0f9i-1309000000-70c9036ae0862b7449de Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 183.69868 predictedDeepCCS 1.0 (2019) [M+H]+ 186.21675 predictedDeepCCS 1.0 (2019) [M+Na]+ 193.47115 predictedDeepCCS 1.0 (2019)
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
- 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
- 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. [Article]
- 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. [Article]
- 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
- 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. [Article]
- FDA Approved Drug Products: Pifeltro (doravirine) oral tablets [Link]
Drug created at October 20, 2016 21:52 / Updated at April 14, 2024 23:44