Rilpivirine

• CAT Number: I009039
• CAS Number: 500287-72-9
• Molecular Formula: C22H18N6
• Molecular Weight: 366.42
• Purity: 98%
• Synonyms: TMC278; TMC278; TMC 278; Rilpivirine; Edurant.;4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile
• Target: HIV
• Target Protein: Q72547
• Solubility: Soluble in DMSO.
• Appearance: Solid
• Storage: Dry, dark and at 2 - 8 °C for six months or -20°C for two years.
• IC50: Rilpivirine have an inhibitory effect in all drug transporters as well as in the cytochrome P450 enzymes, with IC50 values ranging from 1.3–13.1 μM.
• IUPAC Name: 4-[[4-[4-[(E)-2-cyanoethenyl]-2,6-dimethylanilino]pyrimidin-2-yl]amino]benzonitrile
• 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+
• InChIKey: YIBOMRUWOWDFLG-ONEGZZNKSA-N
• SMILES: CC1=CC(=CC(=C1NC2=NC(=NC=C2)NC3=CC=C(C=C3)C#N)C)/C=C/C#N

Rilpivirine(Cat No.:I009039) is an antiretroviral medication used for the treatment of HIV infection. It belongs to the class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rilpivirine is structurally classified as an aminopyrimidine compound, specifically a pyrimidine-2,4-diamine derivative. It is characterized by the substitution of the amino groups at positions 2 and 4 with 4-cyanophenyl and 4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl groups, respectively. Rilpivirine acts as an inhibitor of HIV-1 reverse transcriptase, an enzyme essential for the replication of the virus. It is administered as part of combination therapy to control and manage HIV infection.

Overview of Clinical Research

Originator: Tibotec Pharmaceuticals
Developer: Janssen R&D Ireland; Janssen Therapeutics; National Institute of Allergy and Infectious Diseases; PATH; ViiV Healthcare
Class: Antiretrovirals; Nitriles; Pyrimidines; Small molecules
Mechanism of Action: Non-nucleoside reverse transcriptase inhibitors
Orphan Drug Status: Yes – HIV-1 infections
New Molecular Entity: Yes

Reference

[1]. Drugs. 2018 Nov;78(16):1741-1750. doi: 10.1007/s40265-018-1005-4.
Dolutegravir/Rilpivirine: A Review in HIV-1 Infection.
Blair HA(1).
Author information: (1)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand. .
Dolutegravir/rilpivirine (Juluca®) is the first two-drug single-tablet regimen (STR) to be approved for the treatment of HIV-1 infection in adults. The fixed-dose STR combines the integrase strand transfer inhibitor dolutegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine. In two phase III non-inferiority trials (SWORD-1 and SWORD-2) in treatment-experienced patients already virologically suppressed on their current antiretroviral (ART) regimen, switching to once-daily dolutegravir plus rilpivirine maintained virological suppression over 48 weeks. Switching to a two-drug regimen of dolutegravir plus rilpivirine was also associated with high rates of virological suppression in real-world observational studies. Switching to once-daily dolutegravir plus rilpivirine was generally well tolerated and associated with more favourable renal and bone parameters than remaining on the current ART regimen. Longer-term, dolutegravir plus rilpivirine demonstrated durable maintenance of virological suppression and remained generally well tolerated for up to 100 weeks. Thus, dolutegravir/rilpivirine provides a convenient alternative treatment option for some adults with HIV-1 infection and no history of virological failure who are already virologically suppressed on (and wish to switch from) their current ART regimen.
DOI: 10.1007/s40265-018-1005-4 PMID: 30406902

[2]. Curr Opin HIV AIDS. 2018 Jul;13(4):320-325. doi: 10.1097/COH.0000000000000466.
Dolutegravir-rilpivirine coformulation.
Sun HY(1), Chang SY(2)(3), Hung CC(1)(4)(5)(6).
Author information: (1)Department of Internal Medicine. (2)Department of Laboratory Medicine, National Taiwan University Hospital. (3)Department of Clinical Laboratory Sciences and Medical Biotechnology. (4)Department of Parasitology, National Taiwan University College of Medicine, Taipei. (5)Department of Medical Research, China Medical University Hospital. (6)China Medical University, Taichung, Taiwan.
PURPOSE OF REVIEW: With prolonged life expectancy in HIV-positive patients on combination antiretroviral therapy, the quest for reducing lifelong drug exposure and minimizing or avoiding the toxicities of combination antiretroviral therapy while maintaining viral suppression has emerged when coformulations of antiretroviral agents with improved convenience, and better tolerability and efficacy became available. This review aims to update the current experience with the novel two-drug combination of dolutegravir (DTG) and rilpivirine (RPV) and elucidate the possible applications and limitations of coformulated DTG-RPV in the future. RECENT FINDINGS: Five observational studies and two randomized, noninferiority trials (SWORD-1 and SWORD-2) evaluated the use of DTG and RPV in treatment-experienced patients. Despite variable inclusion criteria, 95-100% of the included patients maintained plasma HIV RNA load less than 50 copies/ml at the end of 24-48 weeks of observation. Overall, this regimen was well tolerated and only 0.8-7.9% of the patients discontinued the regimen due to adverse events. SUMMARY: DTG and RPV is a novel two-drug antiretroviral combination regimen that can be effectively and safely used in patients with viral suppression for 6 months or longer. However, its use in patients with a previous history of virological failure and/or antiretroviral resistance warrants further investigation.
DOI: 10.1097/COH.0000000000000466 PMID: 29553948

[3]. HIV AIDS (Auckl). 2018 Nov 2;10:215-224. doi: 10.2147/HIV.S157855. eCollection 2018.
Dolutegravir/rilpivirine for the treatment of HIV-1 infection.
Dowers E(1), Zamora F(1), Barakat LA(2), Ogbuagu O(2).
Author information: (1)Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, USA. (2)Yale AIDS Program, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA, .
Much progress has been made in the development of antiretroviral therapies (ARTs) for HIV-1 infection. Beginning a little over a decade ago, single tablet combination regimens (STRs) became available, and subsequently, newer STR formulations with improved safety profiles have emerged. Recently, there is a growing interest in regimen simplification with the primary goal of further reducing long-term toxicities of ART and improving medication adherence. Dolutegravir/rilpivirine (DTG/RPV) was approved by the US Food and Drug Administration (FDA) as the first dual antiretroviral STR for the maintenance therapy of HIV-1 infection. Following an extensive review of all published papers on RPV and DTG, administered alone and in combination, extracted from databases including PubMed, Google scholar, and EMBASE, as well as drug package inserts and conference abstracts and proceedings, this review discusses the chemical properties and composition, pharmacodynamics and pharmacokinetic properties, clinical trial efficacy and safety data, as well as important drug-drug interactions associated with DTG/RPV. An expert opinion section discusses ideal candidates for DTG/RPV in the context of available but limited data and in comparison to currently available and emerging ART alternatives.
DOI: 10.2147/HIV.S157855 PMCID: PMC6220428 PMID: 30464642

[4]. Lancet HIV. 2019 Sep;6(9):e560-e561. doi: 10.1016/S2352-3018(19)30188-2. Epub 2019 Jul 12.
Dolutegravir-rilpivirine for virological suppression.
Pozniak AL(1), Arribas JR(2).
Author information: (1)Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK; London School of Hygiene & Tropical Medicine, London, UK. Electronic address: . (2)La Paz Hospital, IdiPaz, Madrid, Spain; Autonoma University School of Medicine, Madrid, Spain.
Comment on Lancet HIV. 2019 Sep;6(9):e576-e587.
DOI: 10.1016/S2352-3018(19)30188-2 PMID: 31307947

[5]. Expert Rev Anti Infect Ther. 2018 Dec;16(12):877-887. doi: 10.1080/14787210.2018.1544491. Epub 2018 Nov 14.
Dolutegravir-rilpivirine: first 2-drug regimen for HIV-positive adults.
Properzi M(1), Magro P(1), Castelli F(1), Quiros-Roldan E(1).
Author information: (1)a Department of Infectious and Tropical Diseases , University of Brescia and ASST Spedali Civili Hospital , Brescia , Italy.
New strategies for HIV treatment are being investigated to reduce drug-exposure, toxicities, and costs. Dolutegravir (DTG) 50 mg/rilpivirine (RPV) 25 mg was approved in November 2017 by FDA and in May 2018 by the European Medicines Agency (EMA). It is indicated as a complete regimen for HIV-1 infected adults with undetectable plasmatic HIV-RNA for at least 6 months on their current HIV treatment combination. Its approval was based on the data of two randomized, multicenter, non-inferiority trials (SWORD-1 and SWORD-2). Areas covered: We reviewed data from literature about DTG and RPV. We mainly focused on the efficacy and on the safety of this new dual therapy. Its impact on renal function, its bone and cardiovascular profile, its reservoir penetration and its role on inflammation were also evaluated. Expert commentary: Dual therapies may be an attractive alternative to standard triple regimens in terms of tolerability and simplicity. Long-term efficacy of DTG and RPV dual regimen need to be confirmed, where only the extensive use of this new treatment and a longer follow-up will give us the answers.
DOI: 10.1080/14787210.2018.1544491 PMID: 30392419