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Rilpivirine (TMC278)
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Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors
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Drug Description |
| TMC278, a diarylpyrimidine derivative, is an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance.[1][2] |
HIV/AIDS-Related Uses |
| TMC278 is being studied in Phase IIb trials for the treatment of HIV infection in treatment-naive patients and in those treatment-experienced patients with drug-resistant HIV.[3] |
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Dosing Information |
Mode of Delivery |
| Oral.[4] |
Dosage Form |
Tablet.[5]
Oral solution.[6]
TMC278 is being studied at 25, 75, and 150 mg daily dosages. The once-daily 75 mg dosage will be developed specifically for use in treatment-naive patients.[7] |
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Pharmacology |
TMC278 is a potent investigational NNRTI with activity against NNRTI-resistant HIV.[8]
TMC278 has strong binding properties and conformational flexibility that allows the drug to overcome mutations conferring NNRTI resistance. Its effective half-life of 38 hours provides for once-daily dosing.[9][10] TMC278 exhibits dose-proportional pharmacokinetic activity over the studied range of 25 to 150 mg once daily. No active metabolites have been discovered. TMC278 is well absorbed, and administration with food increases TMC278 bioavailability by 45%.[11][12][13]
TMC278 has displayed no teratogenicity in trials conducted thus far, unlike some approved NNRTIs that are contraindicated in women who are or may become pregnant.[14]
In a Phase IIa, randomized, double-blind trial examining TMC278 oral solution in 47 treatment-naive, HIV infected male participants, dosages of 25, 50, 100, and 150 mg once daily were administered for 7 days to determine safety, efficacy, and tolerability. Mean viral load levels decreased significantly compared with placebo, by more than 10-fold at Day 7, and no differences were noted among the treatment arms. Plasma concentrations of TMC278 remained above the target concentration of 13.5 ng/ml at all time points. No selection of NNRTI-resistance-associated mutations was observed during the study period.[15][16]
An ongoing, Phase IIb, randomized, active-control, partially-blind trial is evaluating the safety and efficacy of once-daily doses of TMC278 compared with efavirenz in 368 treatment-naive, HIV infected participants. Study arms consisted of 25, 75, or 150 mg TMC278 or of efavirenz 600 mg active control as part of a combination regimen. Treatment and active control arms displayed similar efficacy during and up to Week 48, with viral load reductions of more than 100-fold in the efavirenz control and TMC278 treatment arms. Approximately 80% of patients in all arms reached the primary endpoint of confirmed plasma viral load less than 50 copies/ml at Week 48.[17][18]
When tested against 10 strains of NNRTI-resistant HIV, TMC278 retained a 50% effective concentration against all of the following mutations: L100I, K103N, V106A, G190A, G190S, K101E, Y181C, Y188L, L100I/K103N, and K103N/Y181C. In contrast, the approved NNRTI efavirenz exhibited reduced activity to all but 2 of these mutations. Similarly, in a panel of more than 1,500 NNRTI-resistant isolates of HIV, TMC278 retained at least some activity against most of the isolates, whereas nearly all isolates proved resistant to nevirapine and approximately 40% were highly resistant to efavirenz. Although only 1 mutation was needed to induce nevirapine or efavirenz resistance, 8 mutations were required to reduce susceptibility to TMC278.[19] TMC278 retains activity against HIV with the L100I/K103N and the K103N/Y181C mutations, both of which confer resistance to all FDA-approved NNRTIs.[20] |
Adverse Events/Toxicity |
In a Phase IIa trial that studied 25 to 150 mg doses of TMC278 in treatment-naive, HIV infected participants, rates of adverse events were similar among all TMC278 dose groups and placebo. No serious adverse events occurred. The most common adverse events reported were headache, fatigue, nausea, and somnolence.[21]
In a Phase IIb dose-ranging trial comparing the efficacy and safety of TMC278 to that of efavirenz in a combination regimen, TMC278 was generally well tolerated up to Week 48. The most common adverse events associated with TMC278 were nausea (35%) and headache (18%), both of which occurred more frequently with TMC278 than with efavirenz. Other adverse events, including dizziness, sleepiness, vertigo, rash, and lipid changes, occurred less frequently with TMC278 than with efavirenz. Serious adverse events and Grade 3 or 4 laboratory abnormalities were similar in the TMC278 and efavirenz arms. However, the incidence of Grade 3 or 4 adverse events was 25% in the TMC278 arms compared with 16% in the efavirenz arm.[22][23] |
Drug And Food Interactions |
When 100 mg TMC278 was administered with food to 12 healthy volunteers, the bioavailability of TMC278 increased by 45%; therefore, TMC278 should be administered with food.[24]
When 150 mg TMC278 was coadministered once daily with the cytochrome P450 (CYP) 3A4 substrate ketoconazole 400 mg, the area under the concentration-time curve (AUC) of TMC278 increased by 49%, the Cmax increased by 30%, and the Cmin increased by 76% compared with TMC278 administration alone. The ketoconazole AUC decreased by 24%, and the Cmax and Cmin decreased by 15% and 66%, respectively.[25]
TMC278 is being studied in Phase IIb trials with tenofovir DF and other nucleoside reverse transcriptase inhibitors. When TMC278 was coadministered with tenofovir DF, no clinically relevant interactions were observed.[26] |
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Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use Rilpivirine %20OR%20TMC278. |
Chemistry |
CAS Name |
| Benzonitrile, 4-([4-([4-([1E]-2- cyanoethenyl)- 2,6-dimethylphenyl] amino)- 2-pryimidinyl] amino)-[27] |
CAS Number |
| 500287-72-9[28] |
Molecular Formula |
| C22-H18-N16[29] |
Elemental Composition |
| C52.2%, H3.5%, N44.3%[30] |
Molecular Weight |
| 506[31] |
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Further Reading |
PMID/16931936 Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Bethune MP, Peeters M, Woodfall B. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects. AIDS. 2006 Aug 22;20(13):1721-6.
PMID/15771434 Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, Koymans L, Vinkers M, Guillemont J, Pasquier E, Kukla M, Ludovici D, Andries K, de Bethune MP, Pauwels R, Das K, Clark AD Jr, Frenkel YV, Hughes SH, Medaer B, De Knaep F, Bohets H, De Clerck F, Lampo A, Williams P, Stoffels P. 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.
TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, Abstract 144LB, 2007.
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Manufacturer Information |
Rilpivirine (TMC278)
Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
(877) 732-2488
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References |
[1] Conf Retroviruses Opportunistic Infect - 12th, 2005. Abstract 160.
[2] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract TuPe3.1B10.
[3] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 144LB.
[4] Natap.org - Conference Reports: CROI 2005. Available at: http://www.natap.org/2005/CROI/croi_11.htm. Accessed 06/21/07.
[5] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract TuPe3.1B10.
[6] Natap.org - Conference Reports: CROI 2005. Available at: http://www.natap.org/2005/CROI/croi_11.htm. Accessed 06/21/07.
[7] Natap.org - HIV DENT: TMC278 Matches Efavirenz in Treatment-Naive People. Available at: http://www.hivdent.org/_Medication_/Archives/2007/drugTMET0207.htm. Accessed 06/21/07.
[8] Natap.org - Conference Reports: CROI 2005. Available at: http://www.natap.org/2005/CROI/croi_11.htm. Accessed 06/21/07.
[9] Conf Retroviruses Opportunistic Infect - 12th, 2005. Abstract 556.
[10] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 44.
[11] Conf Retroviruses Opportunistic Infect - 12th, 2005. Abstract 556.
[12] Natap.org - Conference Reports: European HIV Drug Resistance Workshop 2005. Available at: http://www.natap.org/2005/Euro/euro_1.htm. Accessed 06/21/07.
[13] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract TuPe3.1B10.
[14] Natap.org - HIV DENT: TMC278 Matches Efavirenz in Treatment-Naive People. Available at: http://www.hivdent.org/_Medication_/Archives/2007/drugTMET0207.htm. Accessed 06/21/07.
[15] Conf Retroviruses Opportunistic Infect - 12th, 2005. Abstract 160.
[16] AIDS - 2006;20(13):1721-6
[17] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 144LB.
[18] Tibotec - Congresses and News: Tibotec in the News - New data on investigational agent TMC278 in antiretroviral-naive HIV patients [press release], March 1, 2007. Available at: http://www.tibotec.com/news/detail.jhtml?itemname=news_30. Accessed 06/21/07.
[19] Natap.org - Conference Reports: European HIV Drug Resistance Workshop 2005. Available at: http://www.natap.org/2005/Euro/euro_1.htm. Accessed 06/21/07.
[20] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 88.
[21] Natap.org - Conference Reports: CROI 2005. Available at: http://www.natap.org/2005/CROI/croi_11.htm. Accessed 06/21/07.
[22] Natap.org - HIV DENT: TMC278 Matches Efavirenz in Treatment-Naive People. Available at: http://www.hivdent.org/_Medication_/Archives/2007/drugTMET0207.htm. Accessed 06/21/07.
[23] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 144LB.
[24] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract TuPe3.1B10.
[25] Int Conf AIDS - 16th, 2006. Abstract TuPe0087.
[26] IAS Conf on HIV Pathogenesis and Treatment - 3rd, 2005. Abstract WePe3.3C15.
[27] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 06/21/07.
[28] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 06/21/07.
[29] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 06/21/07.
[30] Calculation. -
[31] Calculation. -
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Updated June 21, 2007
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