Rilpivirine

Rilpivirine
Names
Trade namesEdurant, Rekambys
Other namesTMC278
IUPAC name
  • 4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
Clinical data
Drug classNon-nucleoside reverse transcriptase inhibitor (NNRTI)[1]
Main usesHIV/AIDS[1]
Side effectsHeadache, trouble sleeping, dizziness, nausea, abnormal lipid levels, liver problems[1]
Pregnancy
category
  • AU: B1
    Routes of
    use    		By mouth, intramuscular
    Typical dose25 mg OD[2]
    External links
    AHFS/Drugs.comMonograph
    US NLMRilpivirine
    MedlinePlusa611037
    Legal
    License data
    Legal status
    Pharmacokinetics
    Protein binding99.7%
    MetabolismCYP3A4
    Elimination half-lifetablets: 45 hours
    injection: 13–28 weeks
    Excretion85% via faeces, 6% via urine
    Chemical and physical data
    FormulaC22H18N6
    Molar mass366.428 g·mol−1
    3D model (JSmol)
    SMILES
    • Cc1cc(cc(c1Nc2ccnc(n2)Nc3ccc(cc3)C#N)C)/C=C/C#N
    InChI
    • InChI=1S/C22H18N6/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19/h3-9,11-13H,1-2H3,(H2,25,26,27,28)/b4-3+ ☒N
    • Key:YIBOMRUWOWDFLG-ONEGZZNKSA-N ☒N

    • InChI=1S/C22H18N6.ClH/c1-15-12-18(4-3-10-23)13-16(2)21(15)27-20-9-11-25-22(28-20)26-19-7-5-17(14-24)6-8-19;/h3-9,11-13H,1-2H3,(H2,25,26,27,28);1H/b4-3+;
    • Key:KZVVGZKAVZUACK-BJILWQEISA-N

    Rilpivirine, sold under the brand name Edurant among others, is a medication used to treat and prevent HIV/AIDS.[7] Specifically it is used together with other antiviral medication for HIV-1.[1] It is taken by mouth.[2]

    Common side effects include headache, trouble sleeping, dizziness, nausea, abnormal lipid levels, and liver problems.[1] Other side effects may include drug reaction with eosinophilia and systemic symptoms (DRESS) and depression.[7] Use during pregnancy appears safe, but as not been well studied.[8] It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which blocks the enzyme reverse transcriptase.[1]

    Rilpivirine was approved for medical use in the United States and Europe in 2011.[7][1] In the United Kingdom a month of medication costs the NHS about £200 as of 2021.[2] This amount in the United States costs about 1,200 USD.[9]

    Medical uses

    In the US, rilpivirine is approved for treatment-naive patients with a viral load of 100,000 copies/mL or less at therapy initiation. It has to be combined with other drugs against HIV.[10]

    In the European Union, rilpivirine is approved in combination with cabotegravir for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current antiretroviral treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).[6][11]

    Dosage

    It is generally taken at a dose of 25 mg once per day.[2]

    The drug is available as tablets (brand name Edurant) and as a long-acting intramuscular injection to be given once every month or every two months (Rekambys). Before using the injection, the tablets are given for about four weeks to assess tolerability.[10][12]

    Combinations

    A fixed-dose medication combining rilpivirine with emtricitabine and tenofovir disoproxil (TDF) was approved by the U.S. Food and Drug Administration (FDA) in August 2011 under the brand name Complera,[13] and was approved for use in the European Union with the brand name Eviplera in November 2011.[14] This combination has been shown to have higher rates of virologic failure than emtricitabine/tenofovir/efavirenz in people with baseline HIV viral loads greater than 100,000 copies/mm3.

    A fixed-dose medication combining rilpivirine with emtricitabine and tenofovir alafenamide (TAF) was approved for use in the US in March 2016 with the brand name Odefsey.[15]

    In January 2021, the U.S. Food and Drug Administration (FDA) approved cabotegravir/rilpivirine (brand name Cabenuva) for the treatment of HIV-1 infections in adults to replace a current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.[16][17] This is the first FDA-approved injectable, complete regimen for HIV-infected adults that is administered once a month.[16][17] The label for rilpivirine tablets was revised to reflect the oral lead-in recommendations for use with cabotegravir.[17]

    Contraindications and interactions

    The drug is contraindicated for use with drugs that induce the liver enzyme CYP3A4, such as carbamazepine, phenytoin, rifampicin, and St John's wort. Such drugs can accelerate the breaking down of rilpivirine, substantially decreasing its plasma concentrations and potentially resulting in loss of effectiveness and possible resistance.[10] Some of these drugs also induce the enzyme UGT1A1 and thus reduce blood plasma concentrations of cabotegravir, further compromising the effectiveness of this combination therapy.[18]

    It is also contraindicated in combination with proton pump inhibitors because the increased gastric pH causes decreased rilpivirine absorption from the gut, with similar consequences as with CYP3A4 inducers.[10]

    Side effects

    The most common side effects of the injectable formulation are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common (under 10%) are depressive disorders, insomnia, and rashes.[10][12] The most common side effects of the tablets are also depressive disorders (4.1%), headache (3.5%), insomnia (3.5%) and rashes (2.3%).[19] All of these side effects occurred under combination therapies of rilpivirine with one or more other drugs against HIV.

    QT prolongation of the heart rhythm has been observed at very high doses, but is not clinically relevant at standard doses of the drug.[19]

    Pharmacology

    Mechanism of action

    Further information: Reverse-transcriptase inhibitor § Mechanism of action

    Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI).[19]

    Pharmacokinetics

    When taken by mouth, rilpivirine reaches highest levels in the blood plasma after about four to five hours. Taking the drug without food lowers its plasma levels by 40% as compared to taking it with food, which is considered to be clinically relevant. Therefore, patients are advised to take the medication together with a meal.[19] After injection into the muscle, the substance reaches highest plasma levels after three to four days.[12]

    Independently of the mode of application, rilpivirine is almost completely bound to plasma proteins (99.7%), mostly to albumin. It is metabolised mainly by the liver enzyme CYP3A4. Metabolites include several oxidation products, glucuronides, and glucuronides of oxidized metabolites. The biological half-life is approximately 45 hours for the tablets and 13 to 28 weeks for the injection.[12][19]

    Elimination has only been studied for oral administration: Most of the drug is excreted via the faeces (85%), partly in unchanged form (25%), partly in form of its metabolites (60%). A minor amount is excreted via the urine (6%), almost exclusively as metabolites.[12][19]

    One of several metabolism pathways involving the oxidizing enzyme CYP3A4 (and CYP3A5) and the glucuronidizing enzyme UGT1A1.[20]

    Chemistry

    Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine (DAPY).[19]

    The tablets contain rilpivirine hydrochloride,[19] while the injection contains free rilpivirine.[12]

    History

    Rilpivirine entered phase III clinical trials in April 2008,[21][22] and was approved for use in the United States in May 2011 under the brand name Edurant.[23][24]

    On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for rilpivirine under the trade name Rekambys, intended for the treatment of human immunodeficiency virus type-1 (HIV-1) infection in combination with cabotegravir injection.[25] It was approved for medical use in the European Union in December 2020.[6] The two medicines are the first antiretrovirals that come in a long-acting injectable formulation.[11] This means that instead of daily pills, people receive intramuscular injections monthly or every two months.[11]

    References

    1. 1 2 3 4 5 6 7 "Rilpivirine". Archived from the original on 7 January 2021. Retrieved 17 October 2021.
    2. 1 2 3 4 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 683. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    3. ↑ "Edurant 25 mg tablets - Summary of Product Characteristics (SmPC)". (emc). 21 January 2020. Archived from the original on 7 January 2021. Retrieved 4 January 2021.
    4. ↑ "Edurant- rilpivirine hydrochloride tablet, film coated". DailyMed. Archived from the original on 28 October 2020. Retrieved 4 January 2021.
    5. ↑ "Edurant EPAR". European Medicines Agency (EMA). Archived from the original on 7 January 2021. Retrieved 4 January 2021.
    6. 1 2 3 "Rekambys EPAR". European Medicines Agency (EMA). 13 October 2020. Archived from the original on 8 January 2021. Retrieved 4 January 2021.
    7. 1 2 3 "Rilpivirine Monograph for Professionals". Drugs.com. Archived from the original on 10 April 2021. Retrieved 17 October 2021.
    8. ↑ "Rilpivirine (Edurant) Use During Pregnancy". Drugs.com. Archived from the original on 4 December 2020. Retrieved 17 October 2021.
    9. ↑ "Edurant Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 30 July 2015. Retrieved 17 October 2021.
    10. 1 2 3 4 5 Rilpivirine Monograph. Accessed 2021-02-23.
    11. 1 2 3 "First long-acting injectable antiretroviral therapy for HIV recommended approval". European Medicines Agency (EMA) (Press release). 16 October 2020. Archived from the original on 17 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    12. 1 2 3 4 5 6 "Rekambys: EPAR – public assessment report" (PDF). European Medicines Agency. 2021-02-22. Archived (PDF) from the original on 2021-01-12. Retrieved 2021-07-31.
    13. ↑ "Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination". U.S. Food and Drug Administration (FDA). August 10, 2011. Archived from the original on February 8, 2014. Retrieved July 31, 2021.
    14. ↑ "Eviplera". Aidsmap. Archived from the original on January 28, 2019. Retrieved September 1, 2014.
    15. ↑ "Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) Tablets". U.S. Food and Drug Administration (FDA). 29 November 2016. Archived from the original on 13 April 2021. Retrieved 23 January 2021.
    16. 1 2 "FDA Approves First Extended-Release, Injectable Drug Regimen for Adults Living with HIV". U.S. Food and Drug Administration (FDA) (Press release). 21 January 2021. Archived from the original on 21 January 2021. Retrieved 21 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.
    17. 1 2 3 "Cabenuva and Vocabria approved for HIV infection". U.S. Food and Drug Administration (FDA). 27 January 2021. Archived from the original on 27 January 2021. Retrieved 27 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.
    18. ↑ "Vocabria: EPAR – Product information" (PDF). European Medicines Agency. 2021-01-05. Archived (PDF) from the original on 2021-04-10. Retrieved 2021-07-31.
    19. 1 2 3 4 5 6 7 8 "Edurant: EPAR – public assessment report" (PDF). European Medicines Agency. 2021-01-04. Archived (PDF) from the original on 2021-04-10. Retrieved 2021-07-31.
    20. ↑ Lade, Julie M.; Avery, Lindsay B.; Bumpus, Namandjé N. (2013). "Human Biotransformation of the Nonnucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross-Species Metabolism Comparison". Antimicrobial Agents and Chemotherapy. 57 (10): 5067–5079. doi:10.1128/AAC.01401-13. PMC 3811466. PMID 23917319.
    21. ↑ "A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine". ClinicalTrials.gov. National Institutes of Health. October 25, 2012. Archived from the original on January 2, 2014. Retrieved January 1, 2014.
    22. ↑ "A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors". ClinicalTrials.gov. National Institutes of Health. May 14, 2012. Archived from the original on January 2, 2014. Retrieved January 1, 2014.
    23. ↑ "Drug Approval Package: Edurant (rilpivirine) NDA #202022#". U.S. Food and Drug Administration (FDA). 20 August 2013. Archived from the original on 28 March 2021. Retrieved 23 January 2021. Lay summary (PDF). {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
    24. ↑ "FDA approves new HIV treatment" (Press release). U.S. Food and Drug Administration (FDA). Archived from the original on 2017-01-18. Retrieved 2011-05-20.
    25. ↑ "Rekambys: Pending EC decision". European Medicines Agency (EMA). 16 October 2020. Archived from the original on 20 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    • "Rilpivirine". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-05-19. Retrieved 2021-07-31.
    • "Rilpivirine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-01-07. Retrieved 2021-07-31.
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