TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

Vingerhoets, Johan; Azijn, Hilde; Fransen, Els; Baere, Inky De; Smeulders, Liesbet; Jochmans, Dirk; Andries, Koen; Pauwels, Rudi; Béthune, Marie‐Pierre de

doi:10.1128/jvi.79.20.12773-12782.2005

Cited by 229 publications

(196 citation statements)

References 35 publications

(32 reference statements)

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“…As a diarylpyrimidine, ETR has a high capacity for isomerization, which allows it to effectively bind to and inhibit common mutated forms of the viral enzyme (Andries et al, 2004;Vingerhoets et al, 2005;Gupta et al, 2011;Picchio et al, 2011). Therefore, ETR has a higher genetic barrier to viral resistance and as such is often prescribed for treatment-experienced patients who have developed mutations that confer resistance to first-generation NNRTIs (Lazzarin et al, 2007;Madruga et al, 2007;Nadler et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

Yanakakis¹,

Bumpus

2012

Drug Metab Dispos

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ABSTRACT:Etravirine (ETR) is a second-generation non-nucleoside reverse transcriptase inhibitor prescribed for the treatment of HIV-1. By using human liver microsomes (HLMs), cDNA-expressed cytochromes P450 (P450s), and UDP-glucuronosyltransferases (UGTs), the routes of ETR metabolism were defined. Incubations with cDNA-expressed P450 isozymes and chemical inhibition studies using HLMs indicated that CYP2C19 is primarily responsible for the formation of both the major monohydroxylated and dihydroxylated metabolites of ETR. Tandem mass spectrometry suggested that these metabolites were produced via monomethylhydroxylation and dimethylhydroxylation of the dimethylbenzonitrile moiety. Formation of these monohydroxy and dihydroxy metabolites was decreased by 75 and 100%, respectively, in assays performed using HLMs that were genotyped as homozygous for the loss-of-function CYP2C19*2 allele compared with formation by HLMs genotyped as CYP2C19*1/*1. Two monohydroxylated metabolites of lower abundance were formed by CYP3A4, and interestingly, although CYP2C9 showed no activity toward the parent compound, this enzyme appeared to act in concert with CYP3A4 to form two minor dihydroxylated products of ETR. UGT1A3 and UGT1A8 were demonstrated to glucuronidate a CYP3A4-dependent monohydroxylated product. In addition, treatment of primary human hepatocytes with ETR resulted in 3.2-, 5.2-, 11.8-, and 17.9-fold increases in CYP3A4 mRNA levels 6, 12, 24, and 72 h after treatment. The presence of the pregnane X receptor antagonist sulforaphane blocked the ETR-mediated increase in CYP3A4 mRNA expression. Taken together, these data suggest that ETR and ETR metabolites are substrates of CYP2C19, CYP3A4, CYP2C9, UGT1A3, and UGT1A8 and that ETR is a PXR-dependent modulator of CYP3A4 mRNA levels.

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Section: Introductionmentioning

confidence: 99%

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

Yanakakis¹,

Bumpus

2012

Drug Metab Dispos

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“…The findings of this study showed high frequency of the primary NNRTI mutations including K103N, G190A, K103S, Y181Y/C, and Y188L that cause high-level resistance to nevirapine and variable resistance to efavirenz, ranging from 2-fold for Y181C, 6-fold for G190A, 20-fold for K103N and >50-fold for Y188L (29)(30)(31).…”

Section: ------------------------------------------------------------mentioning

confidence: 96%

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART)

Saad

Morimoto²,

Wiechmann³

et al. 2010

Int J Mol Med

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Abstract. The human immunodeficiency virus type 1 (HIV-1) epidemic in Brazil is spreading to small municipalities as well as the innermost parts of the country and scarce information has been reported on the frequency of HIV-1 resistanceassociated mutations in these areas. To determine the frequency and diversity of the HIV-1 antiretroviral resistance-associated mutations among patients failing highly active antiretroviral therapy from Londrina in Southern Brazil, 127 HIV-1 genotyping tests that were assayed during January 2000 to July 2008 from 108 patients were evaluated. Sixty-nine patients (63.9%) were male and 39 (36.1%) were female and the age ranged from 10 to 68 years (mean, 40.8±9.2). All of them showed at least one HIV-1 antiretroviral resistance-associated mutation and in 72 (56.7%) genotyping tests, mutations for the three antiretroviral classes were detected simultaneously. Mutations associated with resistance to protease inhibitor (PI) were detected in 124 tests (97.6%), the main ones were L90M in 28 (22.0%), V82A in 27 (21.2%), M46I in 26 (20.5%), and I54V in 23 (18.1%). The main mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance were M184V in 82 (64.6%), and the thymidine analog mutations were D67N in 51 (40.1%) tests, K70R in 45 (35.4%), T215Y in 40 (31.5%), and M41L in 38 (30.0%). The most frequent major mutations associated with resistance to nonnucleoside RT inhibitors (NNRTI) were K103N in 47 (37.0%), G190A in 11 (8.7%), and G190S in 2 (2.6%) tests. Mutations associated with reduced susceptibility to NRTI and IP simultaneously were observed in 46 (36.2%) tests. The results obtained may contribute to the improvement of the treatment strategies and the management of the antiretroviral drug therapy of HIV-1-infected patients from this Brazilian region, reducing public costs for antiretroviral drugs which have not been efficient in therapy.

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“…[39][40][41] In addition, presence of the K103N (lysine to arginine) mutation that commonly confers resistance to first-generation NNRTIs is not associated with decreased virologic response to etravirine. 42 Seventeen RAMs have been associated with decreased susceptibility to etravirine.…”

Section: Resistancementioning

confidence: 99%

The next generation: etravirine in the treatment of HIV-1 infection in adults refractory to other antiretrovirals

Rathbun¹,

Liedtke

2010

VAAT

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Etravirine is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that is approved for the treatment of adult human immunodeficiency virus (HIV)-infected patients with documented or suspected resistance to first-generation NNRTIs. Etravirine has a flexible molecular structure that allows it to retain its activity against mutant HIV strains that exhibit resistance to first-generation agents. It is evident that 3 or more etravirine resistance-associated mutations are typically necessary before clinical resistance to etravirine. Safety and efficacy of etravirine are established in antiretroviral treatment-experienced patients in combination with antiretroviral regimens that contain darunavir/ritonavir. In phase III studies, cutaneous reactions occurred in 19% of treated patients and are the most commonly observed adverse event. The typical manifestation is the development of a maculopapular rash within the first few weeks of etravirine therapy. Resolution commonly occurs within 1-2 weeks on continued therapy. Rare cases of severe skin reactions (,0.1%) have been reported. Etravirine is hepatically metabolized by cytochrome P450 (CYP) 3A4, CYP2C9, and CYP2C19. Drug interactions with some antiretrovirals (eg, unboosted protease inhibitors and fosamprenavir/ ritonavir) and medications for other comorbidities (eg, atorvastatin and clarithromycin) have been reported and may require dosage adjustment for the coadministered drug or selection of alternative therapy in some instances. Administration of etravirine with potent inducers of CYP450 is not recommended due to the potential for subtherapeutic etravirine concentrations. In this article, the pharmacology, efficacy, safety, and tolerability of etravirine in adult treatmentexperienced patients with HIV-1 infection are reviewed. Medical literature was identified by MEDLINE and EMBASE searches (1966 to February 2010) using the search terms "etravirine", "TMC125", and "NNRTI".

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TMC125 Displays a High Genetic Barrier to the Development of Resistance: Evidence from In Vitro Selection Experiments

Abstract: TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is

Cited by 229 publications

References 35 publications

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

Frequency and diversity of human immunodeficiency virus type 1 mutations associated with antiretroviral resistance among patients from Southern Brazil failing highly active antiretroviral therapy (HAART)

The next generation: etravirine in the treatment of HIV-1 infection in adults refractory to other antiretrovirals

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