TMC278 (rilpivirina) della Tibotec

TMC278 il nuovo NNRTI ha concluso la fase 3 e presto potrebbe essere in commercio.
Funziona come sustiva ma dovrebbe dare meno problemi.


[Devi essere iscritto e connesso per vedere questo link]

Rilpivirine (TMC278)

RSS Feed

Patient VersionHealth Professional VersionSpanish Version
Other Name(s): R278474, Rilpivirina, Rilpivirine
Drug Class: Non-nucleoside Reverse Transcriptase Inhibitors


Drug Description

Rilpivirine, also known as TMC278, is an investigational diarylpyrimidine derivative non-nucleoside reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance in vitro. [1] [2]

References
[1] Conf Retroviruses Opportunistic Infect 12th, 2005. Abstract 160.
[2] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract TuPe3.1B10.

HIV/AIDS-Related Uses

TMC278 as a single agent tablet, in combination with other antiretroviral medications, is being studied in ongoing Phase IIb and Phase III trials for the treatment of HIV infection in treatment-naive patients. [1] [2]

In addition, a fixed-dose single-tablet combination regimen containing TMC278 and emtricitabine/tenofovir disoproxil fumarate is being developed. [3]

References
[1] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 144LB.
[2] Johnson & Johnson – News: All News. Tibotec Pharmaceuticals Submits New Drug Application for Investigational Once-Daily HIV Treatment TMC278 to U.S. Food and Drug Administration [press release], July 26, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[3] Gilead Sciences, Inc. – Newsroom: Press Releases. Gilead Sciences Submits European Marketing Application for Once-Daily Single-Tablet Regimen of Truvada(R) and TMC278 for the Treatment of HIV Infection [press release], September 03, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.

Dosing Information

Mode of Delivery
In clinical trials, TMC278 has been administered orally and via intramuscular and subcutaneous injection. [1] [2] [3]

Dosage Form

In clinical trials, TMC278 has been studied in multiple dosage forms including tablets, oral solution, oral suspension, oral granules, and parenteral injection. [4] [5] [6]

TMC278 is being studied in treatment-naïve patients in an ongoing Phase IIb dose-finding trial at 25, 75, and 150 mg daily dosages. [7]

Two Phase III trials in treatment-naïve patients are evaluating the safety, effectiveness, and tolerability of once-daily TMC278 25 mg, in combination with a background regimen. [8] [9]

In addition, a fixed-dose single-tablet combination regimen containing TMC278 25 mg and emtricitabine 200 mg/tenofovir disoproxil fumarate 245 mg is being developed. [10]





References
[1] Natap.org Conference Reports: CROI 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[2] Int Conf AIDS 17th, 2008. Abstract TUPE0042.
[3] ClinicalTrials.gov – TMC278-TiDP6-C209: A Clinical Trial in Treatment Naive HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed on 12/14/10.
[4] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract TuPe3.1B10.
[5] ClinicalTrials.gov – TMC278-TiDP38-C145: A Bioavailability Study in Healthy Adult Volunteers to Evaluate 3 Pediatric Formulations of TMC278 (a Solution, a Suspension, and Granules) Compared to an Adult Tablet Formulation. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[6] Natap.org Conference Reports: CROI 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[7] ClinicalTrials.gov – TMC278-C204: TMC278 in Treatment Naive HIV-1 Infected Subjects. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[8] ClinicalTrials.gov – TMC278-TiDP6-C209: A Clinical Trial in Treatment Naive HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed on 12/14/10.
[9] ClinicalTrials.gov – TMC278-TiDP6-C215: A Clinical Trial in Treatment Naive HIV-subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[10] Gilead Sciences, Inc. – Newsroom: Press Releases. Gilead Sciences Submits European Marketing Application for Once-Daily Single-Tablet Regimen of Truvada(R) and TMC278 for the Treatment of HIV Infection [press release], September 03, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.

Pharmacology


TMC278 is a potent investigational NNRTI with activity against NNRTI-resistant HIV. [1]

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. [2] [3] [4] 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%. [5] [6] [7]

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. [8]

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 as monotherapy were administered for 7 days to determine safety, efficacy, and tolerability. The primary endpoint of the study was change in HIV-1 RNA viral load from baseline to end of the study period. 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. [9] [10]

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 (EFV) in 368 treatment-naive, HIV-infected participants. Study arms consisted of TMC278 25, 75, or 150 mg versus EFV 600 mg active control, each as part of a combination regimen (zidovudine/lamivudine [AZT/3TC] or tenofovir/emtricitabine [TDF/FTC]). 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 EFV 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. [11] [12] Week 96 follow-up data found that all TMC278 doses resulted in greater than 70% of patients with sustained viral load less than 50 copies/mL, comparable to EFV. Mean CD4 cell increases were 146, 172, and 159 cells/mm3 in the TMC278 25, 75, and 150 mg arms, respectively, compared to 160 cells/mm3 in the EFV group. [13] [14] [15]

ECHO (n = 690) and THRIVE (n = 678) are two ongoing Phase III double-blind, randomized trials in treatment-naïve HIV-infected adults comparing the efficacy, safety and tolerability of once-daily TMC278 25 mg versus once-daily EFV 600 mg, each in combination with a background antiretroviral regimen (ECHO background regimen: TDF/FTC; THRIVE background regimen: TDF/FTC, AZT/3TC, or abacavir [ABC]/3TC) . Both trials met their primary objective, which was to demonstrate non-inferiority (with a 12% maximum allowable difference) of TMC278 versus EFV in confirmed virologic response (viral load <50 copies/mL) at Week 48 (using ITT-TLOVR analysis). Pooled results from both ECHO and THRIVE found that at 48 weeks, 84.3% of patients in the TMC278 group (n = 686) achieved a viral load less than 50 copies/mL, compared with 82.3% in the EFV group (n = 682). The mean increase in CD4 cell count from baseline to Week 48 was 192 and 176 cells/mm3 for TMC278 and EFV, respectively. Virologic failure occurred in 9.0% and 4.8% of TMC278 and EFV patients, respectively (ITT-TLOVR analysis up to Week 48). Nucleoside reverse transcriptase inhibitor (NRTI) background regimens had no reported effect on virologic response. [16] [17] [18]

A 48-week pooled analysis of resistance among patients failing treatment in both ECHO and THRIVE demonstrated that 10% of TMC278 participants (n = 686) and 6% of EFV participants (n = 682) experienced virologic failure (ITT population with data beyond Week 48). Investigators report that increased virologic failure rates in both treatment groups was associated with sub-optimal adherence and/or higher baseline viral load; this effect was more apparent in the TMC278 arm than in the EFV arm. Treatment-emergent NNRTI resistance-associated mutations were seen in 63% of patients with virologic failure in the TMC278 arm, compared with 54% in the EFV arm (sample sizes limited to patients having both virologic failure with resistance data at time of failure; TMC278 n = 62 and EFV n = 28). Treatment-emergent IAS-USA NRTI resistance-associated mutations developed in 68% and 32% of TMC278 and EFV patients with virologic failure, respectively. The most frequently observed emergent NNRTI resistance-associated mutations among the TMC278 virologic failures were E138K, K101E and H221Y. The proportion of virologic failures with M184 mutations was greater in the TMC278 group, compared to the EFV group. [19] [20] [21] [22] [23]

In a resistance analysis of TMC278, 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. [24] TMC278 retains activity against HIV with the L100I/K103N and the K103N/Y181C mutations, both of which confer resistance to all FDA-approved NNRTIs. [25]


References
[1] Natap.org Conference Reports: CROI 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[2] Conf Retroviruses Opportunistic Infect 12th, 2005. Abstract 556.
[3] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 44.
[4] Natap.org Conference Reports: CROI 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[5] Conf Retroviruses Opportunistic Infect 12th, 2005. Abstract 556.
[6] Natap.org Conference Reports: European HIV Drug Resistance Workshop 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[7] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract TuPe3.1B10.
[8] Natap.org HIV DENT: TMC278 Matches Efavirenz in Treatment-Naive People. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[9] Conf Retroviruses Opportunistic Infect 12th, 2005. Abstract 160.
[10] AIDS 2006;20(13):1721-6
[11] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 144LB.
[12] 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: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[13] Int Conf AIDS 17th, 2008. Abstract TUAB0103.
[14] HIV and Hepatitis.com – Investigational Next-generation NNRTI Rilpivirine (TMC278) Demonstrates Potent Antiviral Activity at 96 Weeks in Treatment-naïve Patients. Coverage of the XVII International AIDS Conference (AIDS 2008), August 3-8, 2008. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[15] Tibotec Pharmaceuticals – Tibotec in the News. Ninety-six Week Data on Tibotec Investigational NNRTI, TMC278, Presented at AIDS 2008 [press release], August 5, 2008. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[16] Int Conf AIDS 18th, 2010. Abstract THLBB206.
[17] Tibotec Pharmaceuticals – Tibotec in the News. TMC278 Pivitol Phase 3 Clinical Trials Achieve Primary Objective [press release], July 22, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[18] HIV and Hepatitis.com – New NNRTI Rilpivirine (TMC278) Shows Potent Antiviral Activity and Good Tolerability in Phase 3 Trials, FDA Application Submitted. Coverage of the XVIII International AIDS Conference (AIDS 2010), July 18-23, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[19] Int Conf AIDS 18th, 2010. Abstract THLBB206.
[20] Tibotec Pharmaceuticals – Tibotec in the News. TMC278 Pivitol Phase 3 Clinical Trials Achieve Primary Objective [press release], July 22, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[21] HIV and Hepatitis.com – Rilpivirine Failure Linked to High Viral Load and Poor Adherence. Coverage of the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010), September 12-15, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[22] Intersci Conf Antimicrob Agents Chemother 50th, 2010. Abstract H-1810.
[23] Int Conf AIDS 18th, 2010. Abstract THLBB206.
[24] Natap.org Conference Reports: European HIV Drug Resistance Workshop 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[25] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 88.

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. [1]

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 96. The incidence of serious adverse events, Grade 3 or 4 adverse events and Grade 3 or 4 laboratory abnormalities in the TMC278 combined arms (all doses) versus the EFV arm were 12.2% versus 14.6%, 27.2% versus 21.3%, and 26.5% versus 23.6%, respectively. Patients receiving TMC278 were reported as less likely than those receiving EFV to experience rash (9.7% vs 22.5%), CNS events (36.6% vs 53.9%), and psychiatric events (16.1% vs 21.3%). Triglyceride levels decreased by approximately 10 mg/dL in the TMC278 group, compared with a 29 mg/dL increase in the EFV group. [2] [3] [4]

Pooled Week 48 adverse events data from two Phase III trials, ECHO and THRIVE, found that the incidence of serious adverse events, Grades 2 to 4 adverse events (possibly related to treatment), and discontinuations due to adverse events in the TMC278 and EFV arms were 7% versus 8%, 16% versus 31%, and 3 % versus 8%, respectively. The most common adverse events occurring in the TMC278 and EFV arms were neurological (17% vs 38%), including dizziness (8% vs 26%), and psychiatric (15% vs 23%), including abnormal dreams/nightmares (8% vs 13%). Rash of any type was reported in 3% of TMC278 patients, compared with 14% of EFV patients. 10.9% and 17.6% of patients experienced Grade 3 or 4 laboratory abnormalities in the TMC278 and EFV arms, respectively. TMC278 exhibited lower incidences of increased ALT (1.5% vs 3.4%), LDL (0.7% vs 4.1%), triglycerides (0.3% vs 2.2%), and total cholesterol (0.1% vs 2.5%), compared with EFV. Investigators report a minimal change in mean serum creatinine in both groups and no observed differences in QTc interval changes between TMC278 and EFV treatment groups. [5] [6] [7]

References
[1] Natap.org Conference Reports: CROI 2005. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[2] Int Conf AIDS 17th, 2008. Abstract TUAB0103.
[3] HIV and Hepatitis.com – Investigational Next-generation NNRTI Rilpivirine (TMC278) Demonstrates Potent Antiviral Activity at 96 Weeks in Treatment-naïve Patients. Coverage of the XVII International AIDS Conference (AIDS 2008), August 3-8, 2008. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[4] Tibotec Pharmaceuticals – Tibotec in the News. Ninety-six Week Data on Tibotec Investigational NNRTI, TMC278, Presented at AIDS 2008 [press release], August 5, 2008. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[5] Int Conf AIDS 18th, 2010. Abstract THLBB206.
[6] Tibotec Pharmaceuticals – Tibotec in the News. TMC278 Pivitol Phase 3 Clinical Trials Achieve Primary Objective [press release], July 22, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[7] HIV and Hepatitis.com – New NNRTI Rilpivirine (TMC278) Shows Potent Antiviral Activity and Good Tolerability in Phase 3 Trials, FDA Application Submitted. Coverage of the XVIII International AIDS Conference (AIDS 2010), July 18-23, 2010. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.

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. [1]

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 peak plasma concentration (Cmax) increased by 30%, and the minimum plasma concentration (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. [2]

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. [3]

A study of darunavir 800 mg/ritonavir 100 mg coadministered with TMC278 150 mg in 16 healthy subjects demonstrated that darunavir/ritonavir increased the AUC, Cmax, and Cmin of rilpivirine by 230%, 79%, and 278%, respectively. TMC278 had no clinically relevant effect on darunavir/ritonavir pharmacokinetics. [4]

The solubility of TMC278 is reported to decrease in solutions with increasing pH. Coadministration of drugs that increase gastric pH may interfere with TMC278 absorption. [5]



References
[1] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract TuPe3.1B10.
[2] Int Conf AIDS 16th, 2006. Abstract TuPe0087.
[3] IAS Conf on HIV Pathogenesis and Treatment 3rd, 2005. Abstract WePe3.3C15.
[4] Clin Pharmacokinet. 2009; 48(4): 211-41.
[5] Clin Pharmacokinet. 2009; 48(4): 211-41.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Rilpivirine (TMC278).


Chemistry

CAS Name
Benzonitrile, 4-([4-([4-([1E]-2- cyanoethenyl)- 2,6-dimethylphenyl] amino)- 2-pryimidinyl] amino)- [1]

CAS Number
500287-72-9 [2]

Molecular Formula
C22-H18-N6 [3]

Elemental Composition
C72.0%, H5.0%, N23.0%

Molecular Weight

366.43 [4]




References
[1] ChemIDplus Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[2] ChemIDplus Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[3] ChemIDplus Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.
[4] National Institute of Allergy and Infectious Diseases: Division of AIDS Anti-HIV/OI/TB Therapeutics Database. Available at: [Devi essere iscritto e connesso per vedere questo link] Accessed 12/14/10.

Further Reading



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.

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.

Pooled Week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, Phase III trials comparing TMC278 versus efavirenz in treatment-naïve, HIV-1-infected patients. XVIII International AIDS Conference, Vienna Austria. Abstract THLBB206, 2010.

Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA. Abstract H-1810, 2010.




Manufacturer Information

Rilpivirine (TMC278)
Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA 19067
Phone: 877-732-2488