Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etravirine [TMC 125] is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by Tibotec (Tibotec-Virco Group; now Johnson & Johnson) for the treatment of HIV-1 infections. Etravirine is a highly flexible, di-aryl-pyrimidine (DAPY) compound. The flexibility enables favourable binding interactions with mutant HIV strains as well as wild-type virus. Etravirine has superseded dapivirine as Tibotec's lead NNRTI in clinical development worldwide. Tibotec merged with Virco to form Tibotec-Virco Group in March 2001. Subsequently, Tibotec-Virco Group was acquired by Johnson & Johnson on 18 April 2002. Etravirine was discovered by Tibotec in collaboration with the Janssen Research Foundation. However, the Janssen Research Foundation is no longer involved in the development of etravirine. Etravirine has received fast-track status from the US FDA for the treatment of HIV-1 infections. An expanded access programme for etravirine began in the US in September 2006. The programme made etravirine available to HIV-1 infected adults who have limited treatment options due to virological failure or intolerance to multiple antiretroviral regimens. The progamme will also be introduced in Canada and Europe. In November 2005, Tibotec initiated two randomised, placebo-controlled phase III trials of etravirine in treatment-experienced HIV-1 infected patients with NNRTI resistance and at least three primary protease mutations. The two trials will each enroll 600 patients and will be conducted in 18 countries. Darunavir will be used as the background protease inhibitor in the trials. This is the first time that two investigational antivirals have been evaluated in combination in heavily treatment-experienced patients. The trial design is supported by the FDA, the Committee for Medicinal Products for Human Use (CHMP) of the EMEA and the HIV patient community. Patient enrolment in the two phase III trials was completed in September 2006. A multicentre phase IIb dose-finding study (TMC125 C223) in Europe, Canada and the US found etravirine significantly reduced the HIV viral load in a subset of heavily treatment-experienced patients. Tibotec discontinued a single exploratory open-label phase II trial (TMC 125-C227) of etravirine in November 2005. The discontinuation was a result of 12-week data, which demonstrated a difference in the proportion of patients achieving or maintaining undetectable viral load in favour of the control group, who were receiving protease inhibitor-based treatment. There were no safety concerns and the discontinuation had no effect on phase III registration trials. Phase IIa clinical trials of etravirine for the treatment of HIV infections, initiated in November 2001, have been completed. Tibotec has conducted a phase I trial (TMC125-C157 study) evaluating etravirine + didanosine among healthy volunteers in Belgium; trial results have been presented.
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PMID:Etravirine: R165335, TMC 125, TMC-125, TMC125. 1707 19

Etravirine, formerly known as TMC 125, is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against HIV resistant to currently licensed NNRTIs. It is in its final stage of clinical development and has received fast-track status for review by the U.S. Food and Drug Administration (FDA). In randomized placebo-controlled trials in treatment-experienced patients with confirmed NNRTI resistance, it has shown virological efficacy superior to the control arms with comparable rates of adverse events with the exception of rash. Because of its effect on the cytochrome P450 system, there are significant drug interaction issues that will need to be taken into consideration with its use.
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PMID:Etravirine. 1830 1

Etravirine is a next generation nonnucleoside reverse transcriptase inhibitor with activity against nonnucleoside reverse transcriptase inhibitor resistant HIV-1 virus. Susceptibility and virological response to etravirine is dependent on the type and number of nonnucleoside reverse transcriptase inhibitor resistance-associated mutations. We examined the predicted susceptibility of etravirine in patients experiencing virological failure secondary to nonnucleoside reverse transcriptase inhibitor resistance in our patient cohort.
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PMID:Is there a role for etravirine in patients with Nonnucleoside reverse transcriptase inhibitor resistance? 1845 59

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.
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PMID:Etravirine for the treatment of HIV infection. 1866 9

Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC(0-12)), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C(max)), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C(12)); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC(0-12), 1.04 (0.97, 1.12) for C(max), and 1.17 (1.10, 1.26) for C(12). All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.
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PMID:Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. 1883 86

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that demonstrates potent in vitro activity against wild-type strains of HIV type 1 (HIV-1), as well as against numerous strains resistant to available NNRTIs. Furthermore, the potential for resistance to etravirine developing appears to be lower than for first-generation NNRTIs. In treatment-experienced patients infected with HIV-1 with NNRTI resistance, HIV-1 RNA levels of <50 copies/mL (primary endpoint) and <400 copies/mL were achieved by a significantly greater proportion of patients receiving etravirine 200 mg twice daily plus background therapy (BT) than placebo plus BT, according to the planned pooled and individual 24-week analyses of two large, well designed, continuing phase III trials (DUET-1 and DUET-2). In the pooled 24-week analysis, patients receiving etravirine plus BT achieved a significantly greater mean reduction in viral load from baseline and a significantly greater mean increase in CD4+ cell counts from baseline than patients receiving placebo plus BT. The pooled and individual findings of the DUET studies at 48 weeks indicate that the efficacy of etravirine is maintained with regard to these endpoints. In the DUET studies, etravirine was generally well tolerated in treatment-experienced patients infected with HIV-1, with a tolerability profile generally similar to that of placebo. Adverse events were mostly of mild or moderate severity.
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PMID:Etravirine. 1897 98

For the quantification of the novel non-nucleoside reverse transcriptase inhibitor etravirine in human plasma, dried blood spots and peripheral blood mononuclear cell (PBMC) lysate, an assay was developed and validated, using liquid chromatography coupled with tandem mass spectrometry. Etravirine was extracted from plasma by means of protein precipitation with a mixture of methanol and acetonitrile using only 50 microL plasma. Extraction from dried blood spots was performed with a one-step extraction with a mixture of methanol, acetonitrile and 0.2M zinc sulphate in water (1:1:2, v/v/v) and extraction from cell lysate was performed in 50% methanol in water. Chromatographic separation was performed on a reversed phase C18 column (150mmx2.0mm, particle size 5microm) with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.25mL/min. (13)C(6)-efavirenz was used as an internal standard. The analytical run time was only 10min. The triple quadrupole mass spectrometer was operated in the positive ion-mode and multiple reaction monitoring was used for drug quantification. The method was validated over a range of 25-5000ng/mL in plasma, 50-10,000ng/mL in dried blood spots and a range of 5-2500ng/mL in PBMC lysate. Accuracies ranged from 89% to 106% in plasma, from 94% to 109% in dried blood spots and from 91% to 105% in PBMC lysate. Precisions at the all concentration levels ranged from 1.9% to 14% in plasma, 4.7% to 20% in dried blood spots and from 3.1% to 11% in PBMC lysate. The bioanalytical assay was successfully incorporated with previously developed assays for the determination of all currently approved PIs and NNRTIs in plasma and dried blood spots and it is now applied for therapeutic drug monitoring and pharmacological research in HIV-infected patients treated with etravirine.
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PMID:Quantification of etravirine (TMC125) in plasma, dried blood spots and peripheral blood mononuclear cell lysate by liquid chromatography tandem mass spectrometry. 1905 44

Forty-eight-week results from a randomized, multicentre, part-blinded, phase IIb clinical trial assessing the efficacy and safety of 400 and 800 mg etravirine twice daily (phase IIb formulation) and optimized background regimen versus standard-of-care regimen are presented. Both etravirine doses demonstrated sustained virological suppression at 48 weeks and a favourable tolerability profile. Etravirine demonstrated higher efficacy than control, irrespective of the number of detectable nonnucleoside reverse transcriptase inhibitor-resistance-associated mutations at baseline or active background antiretrovirals.
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PMID:Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial. 1911 52

Etravirine and rilpivirine are two new nonnucleoside reverse transcriptase inhibitors (NNRTIs) that have the distinct advantage of being able to be used in patients with exposure to previous NNRTIs (e.g., nevirapine or efavirenz). Etravirine was approved by the United States Food and Drug Administration to be used twice/day in treatment-experienced patients infected with the human immunodeficiency virus. The approval was based on phase III clinical studies in which 61% of etravirine-treated patients reached an undetectable viral load of less than 50 copies/ml compared with 40% of patients who received the optimized background regimen. Etravirine was well tolerated with a self-limiting skin rash being the most common toxicity, reported in 19% of patients. Rilpivirine, a once-daily NNRTI, is entering phase III studies; the drug appears to be effective against a broad range of NNRTI-resistant viruses including etravirine-resistant strains.
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PMID:Etravirine and rilpivirine: nonnucleoside reverse transcriptase inhibitors with activity against human immunodeficiency virus type 1 strains resistant to previous nonnucleoside agents. 1924 47

We investigated the phenotypic impact of a number of uncommon amino acid substitutions at HIV-1 reverse transcriptase positions 103 and 138, which are not part of the etravirine resistance score and were found in combination with the high-impact mutation K101P. Etravirine phenotypic fold changes were 380-1400 for K101P + E138A/G/Q + K103N/S/T + V179I and 12-130 for K101P + (K103S +/- V179I) in the absence of E138A/G/Q. Although the effect of K103S is unclear, additional position 138 substitutions seem important for etravirine susceptibility.
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PMID:Additional HIV-1 mutation patterns associated with reduced phenotypic susceptibility to etravirine in clinical samples. 1947 48


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