All single and double mutants tested (EC50=0.1-2.0 nM) and wild-type HIV-1 (EC50=0.4 nM) are both susceptible to R278474's activity[1]. Within 30 days, R278474 (10-5000 nM; 30 d) does not show any indication of wild-type HIV-1 breakthrough at 1 μM[1]. At a 50% inhibitory concentration (EC50) of less than 1 nM, R278474 inhibits 81% of clinical isolates (about 1200 recombinant clinical isolates), and at an EC50 of less than 10 nM, it inhibits 94%[1]. TMC278 exhibits nanomolar EC50s (2.88-8.45 nM) against group O isolates and subnanomolar EC50s (0.07-1.01 nM) against wild-type HIV-1 group M isolates in MT4 T-cells[2].

Rats treated with R278474 (10-160 mg/kg; po for 1 month) do not exhibit any aberrant effects, with the exception of increased liver weight and species-specific thyroid hypertrophy at higher dose levels[1]. In rats, R278474 (iv) has elimination half-lives ranging from 4.4 hours to 31 hours. In dogs, the exposure (AUCinf) is 8.7 hours per kilogram (1.25 mg/kg), 1.4 hours per kilogram (1.25 mg/kg), and 44 hours per kilogram (1.25 mg/kg) in rabbits[1]. In rats and dogs, R278474 (po) had half-live ranges of 2.8 and 39 hours, respectively, with oral bioavailability of 32% and 31%[1].

Absorption, Distribution and Excretion
Rilpivirine has a Tmax of 3-4 hours and has a mean AUC of 2235 ± 851 ng\*h/mL. A 25mg dose reaches a Cmax of 247 ng/mL in healthy subjects and 138.6 ng/mL in patients with HIV-1.
Rilpivirine is 85% eliminated in the feces and 6.1% eliminated in the urine. 25% of a dose is recovered in the feces as the unchanged parent drug, while <1% of a dose is recovered in the urine as the unchanged parent drug.
In HIV-1 patients, the apparent volume of distribution in the central compartment was 152-173 L.
In HIV-1 patients, the apparent total clearance is estimated to be 6.89-8.66 L/h.
After a single oral dose, an average of 85% of the dose is eliminated in feces (75% as metabolites) and 6% is eliminated in urine (only trace amounts as unchanged rilpivirine).
It is not known whether rilpivirine is distributed into human milk; however, the drug is distributed into milk in rats.

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Metabolism / Metabolites
Rilpivirine is predominantly metabolized by CYP3A4 and CYP3A5 to the hydroxylated metabolites M1, M2, M3, and M4. UGT1A1 glucuronidates the M2 metabolite to form M6, UGT1A4 glucuronidates rilpivirine to form M5, and an unknown UGT glucuronidates the M4 metabolite to form M7.
Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.

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Biological Half-Life
Rilpivirine has a terminal half-life of 34-55 hours.
The terminal elimination half-life of rilpivirine is approximately 50 hours.

Hepatotoxicity
Serum aminotransferase elevations occur in 25% or more of patients on rilpivirine therapy, but elevations above 5 times the upper limit of normal are uncommon, occurring in 1% to 4% of patients. The rate of serum aminotransferase elevations during rilpivirine therapy is higher in patients who are coinfected with hepatitis B or C [~10% have values greater than 5 times ULN]. The product label for rilpivirine induces a warning about hepatotoxicity particularly in patients with HBV or HCV coinfection and recommends monitoring for liver test abnormalities. During the first several years of wide spread clinical use of rilpivirine, a single case report of liver injury was published. The case was marked by prominent elevations in serum ALT and AST without jaundice arising within days of starting therapy and resolving rapidly upon stopping (Case 1). There was no rash, eosinophilia or other prominent immunoallergic features which are typical of the liver injury associated with nevirapine and efavirenz. Thus, clinically apparent hepatotoxicity due to rilpivirine may occur but is rare.
Liklihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal rilpivirine doses of 25 mg daily produce low levels in milk and infant serum. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Rilpivirine is >99% bound to plasma protein, most commonly albumin.

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Interactions
Concomitant use of omeprazole and rilpivirine has resulted in decreased rilpivirine plasma concentrations and AUC. Concomitant use of other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations. Concomitant use of rilpivirine and proton-pump inhibitors is contraindicated.
Concomitant use of famotidine and rilpivirine has resulted in decreased rilpivirine plasma concentrations and area under the concentration-time curve (AUC). Concomitant use of other histamine H2-receptor antagonists (e.g., cimetidine, nizatidine, ranitidine) also may result in decreased rilpivirine plasma concentrations. Rilpivirine and histamine H2-receptor antagonists should be used concomitantly with caution; histamine H2-receptor antagonists should be administered at least 12 hours before or at least 4 hours after rilpivirine.
Potential pharmacokinetic interaction with antacids such as aluminum hydroxide, calcium carbonate, or magnesium hydroxide (decreased plasma rilpivirine concentrations). Antacids and rilpivirine should be used concomitantly with caution; antacids should be administered at least 2 hours before or at least 4 hours after rilpivirine.
Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A. Concomitant use with drugs that induce CYP3A may result in decreased plasma rilpivirine concentrations and may result in possible loss of virologic response and development of resistance to rilpivirine or the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. Concomitant use with drugs that inhibit CYP3A may result in increased plasma rilpivirine concentrations. When the recommended rilpivirine dosage (25 mg once daily) is used, it is unlikely to have clinically important effects on the pharmacokinetics of drugs that are metabolized by CYP isoenzymes.

[1]. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem. 2005 Mar 24;48(6):1901-9.

[2]. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother. 2010 Feb;54(2):718-27.

Therapeutic Uses
HIV Reverse Transcriptase/antagonists & inhibitors
Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>/= 3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.

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Drug Warnings
Adverse effects of moderate or severe intensity and reported in 2% or more of patients receiving rilpivirine include depressive disorders, insomnia, headache, and rash. Increased serum AST and/or ALT concentrations (more than 2.5 times the upper limit of normal (ULN) were reported in 3-4% of patients receiving rilpivirine.
Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease since concentrations of the drug may be increased due to alterations in absorption, distribution, or metabolism.
Rilpivirine and the fixed combination containing rilpivirine, emtricitabine, and tenofovir (Complera) have not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic and/or renal function and potential for concomitant disease and drug therapy.
For more Drug Warnings (Complete) data for Rilpivirine (13 total), please visit the HSDB record page.

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Pharmacodynamics
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity reactions, hepatotoxicity, depressive disorders, and the redistribution or accumulation of body fat.

C22H18N6

366.42

366.159

500287-72-9

Rilpivirine hydrochloride;700361-47-3;Rilpivirine-d6;1312424-26-2

6451164

Light yellow to yellow solid powder

1.3±0.1 g/cm3

634.1±65.0 °C at 760 mmHg

245ºC

337.3±34.3 °C

0.0±1.9 mmHg at 25°C

1.665

3.63

2

6

5

28

607

0

CC1=CC(=CC(=C1NC2=NC(=NC=C2)NC3=CC=C(C=C3)C#N)C)/C=C/C#N

YIBOMRUWOWDFLG-ONEGZZNKSA-N

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+

4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 3 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 3 mg/mL (8.19 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3 mg/mL (8.19 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)