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Thomas N Kakuda - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and Pharmacodynamics of Etravirine 400 mg Once Daily in Treatment-Naïve Patients
Hiv Clinical Trials, 2020Co-Authors: Giovanni Di Perri, Yvon Van Delft, Bruce Green, Glynn A. Morrish, Andrew Hill, Gerd Faetkenheuer, Markus Bickel, Michael Kurowski, Thomas N KakudaAbstract:AbstractBackground: Etravirine is currently approved for HIV treatment–experienced patients at a dose of 200 mg twice daily. The long terminal elimination half-life of Etravirine should support once-daily dosing.Methods: In the double-blind 48-week SENSE trial, 157 antiretroviral treatment–naive patients were randomly assigned to receive Etravirine 400 mg once daily (n = 79) or efavirenz 600 mg once daily (n = 78), plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). Sparse sampling for Etravirine plasma concentrations was conducted during the 48-week trial. Area under the curve over the dosing interval (AUC24) and trough concentration (C0) were estimated using a population pharmacokinetic model and compared with previous results using the 200-mg twice-daily dosage. The relationship between Etravirine AUC24 and C0 with efficacy and safety was also assessed.Results: By week 48, the percentage of patients in the Etravirine arm with HIV RNA
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Original research article Effect of steady-state Etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone ☆,☆☆,★
2020Co-Authors: Monika Schöller-gyüre, Thomas N Kakuda, Monika Peeters, Brian Woodfall, Fatima Aharchi, Kati VandermeulenAbstract:Background: Etravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) active against NNRTI-resistant HIV, is an inducer of CYP3A4 and an inhibitor of CYP2C9/19. Study Design: The effect of Etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone was assessed in 30 HIV-negative females. Following a run-in cycle with ethinylestradiol/norethindrone, the pharmacokinetics of ethinylestradiol and norethindrone was assessed on Day 15 of Cycle 2. Etravirine 200 mg bid was coadministered on Day 1 to Day 15 of Cycle 3, with pharmacokinetic assessments of ethinylestradiol, norethindrone and Etravirine on Day 15. Results: When combined with Etravirine, the least-squares means (LSM) ratios (90% confidence interval) for ethinylestradiol AUC24h, Cmax and Cmin were 1.22 (1.13–1.31), 1.33 (1.21–1.46) and 1.09 (1.01–1.18), respectively, compared to administration alone. LSM ratios for norethindrone parameters were 0.95 (0.90–0.99), 1.05 (0.98–1.12) and 0.78 (0.68–0.90), respectively. Conclusion: These changes are not considered clinically relevant. No loss in contraceptive efficacy is expected when coadministered with Etravirine.
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Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine
Clinical Pharmacokinectics, 2016Co-Authors: Bruce Green, Thomas N Kakuda, Herta Crauwels, Simon Vanveggel, Anne BrochotAbstract:Background Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of Etravirine.
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pharmacokinetics of Etravirine combined with atazanavir ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment experienced hiv 1 infected patients
Aids Research and Treatment, 2015Co-Authors: Catherine Orrell, Thomas N Kakuda, Steven Nijs, Lotke Tambuyzer, Franco Felizarta, Andre Nell, Ludo Lavreys, Rodica Van Solingenristea, F TomakaAbstract:Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between Etravirine and atazanavir/ritonavir and safety and efficacy in treatment-experienced, HIV-1-infected patients. Methods. After a two-week lead-in of two nucleoside reverse transcriptase inhibitors (NRTIs) and atazanavir/ritonavir 300/100 mg, 44 patients received Etravirine 200 mg bid with one NRTI, plus atazanavir/ritonavir 300/100 mg or 400/100 mg qd ( each group) over 48 weeks. Results. At steady-state Etravirine with atazanavir/ritonavir 300/100 mg qd or 400/100 mg qd decreased atazanavir by 18% and 9%, respectively, with no change in or versus atazanavir/ritonavir 300/100 mg qd alone (Day −1). Etravirine was 24% higher and 16% lower with atazanavir/ritonavir 300/100 or 400/100 mg qd, respectively, versus historical controls. At Week 48, no significant differences were seen between the atazanavir/ritonavir groups in discontinuations due to adverse events (9.1% each group) and other safety parameters, the proportion of patients with viral load <50 copies/mL (intent-to-treat population, noncompleter = failure) (50.0%, atazanavir/ritonavir 300/100 mg qd versus 45.5%, 400/100 mg qd), and virologic failures (31.8% versus 27.3%, resp.). Conclusions. Etravirine 200 mg bid can be combined with atazanavir/ritonavir 300/100 mg qd and an NRTI in HIV-1-infected, treatment-experienced patients without dose adjustment.
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Etravirine in treatment experienced hiv 1 infected children and adolescents 48 week safety efficacy and resistance analysis of the phase ii piano study
Hiv Medicine, 2014Co-Authors: Gareth Tudorwilliams, Thomas N Kakuda, Steven Nijs, Pedro Cahn, Kulkanya Chokephaibulkit, Jan Fourie, C Karatzios, S Dincq, Magda Opsomer, Lotke TambuyzerAbstract:ObjectivesPIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of Etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (6 to 95%, male sex, low baseline Etravirine weighted genotypic score and high Etravirine trough concentration (C-0h). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were >95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean Etravirine area under the plasma concentration-time curve over 12h (AUC(0-12h); 5216ng h/mL) and C-0h (346ng/mL) were comparable to adult target values. ConclusionsResults with Etravirine 5.2mg/kg bid (with OBR) in this treatment-experienced paediatric population and Etravirine 200mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients
Steven Nijs - One of the best experts on this subject based on the ideXlab platform.
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Virological response with fully active Etravirine: Pooled results from the DUET-1 and DUET-2 trials
International Journal of Std & Aids, 2020Co-Authors: Nathan Clumeck, Steven Nijs, Johan Vingerhoets, Pedro Cahn, Jean-michel Molina, Anthony A. Mills, James WitekAbstract:The objective of this subanalysis of the Phase III DUET trials was to examine virological response to an Etravirine-containing regimen in patients harbouring virus fully sensitive to Etravirine. Full Etravirine sensitivity was defined as fold change in 50% effective concentration (FC) ≤3 or weighted genotypic score ≤2. At Week 48 in the Etravirine group, 74% of patients with Etravirine FC ≤3 and 77% with Etravirine genotypic score ≤2 had viral load
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pharmacokinetics of Etravirine combined with atazanavir ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment experienced hiv 1 infected patients
Aids Research and Treatment, 2015Co-Authors: Catherine Orrell, Thomas N Kakuda, Steven Nijs, Lotke Tambuyzer, Franco Felizarta, Andre Nell, Ludo Lavreys, Rodica Van Solingenristea, F TomakaAbstract:Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between Etravirine and atazanavir/ritonavir and safety and efficacy in treatment-experienced, HIV-1-infected patients. Methods. After a two-week lead-in of two nucleoside reverse transcriptase inhibitors (NRTIs) and atazanavir/ritonavir 300/100 mg, 44 patients received Etravirine 200 mg bid with one NRTI, plus atazanavir/ritonavir 300/100 mg or 400/100 mg qd ( each group) over 48 weeks. Results. At steady-state Etravirine with atazanavir/ritonavir 300/100 mg qd or 400/100 mg qd decreased atazanavir by 18% and 9%, respectively, with no change in or versus atazanavir/ritonavir 300/100 mg qd alone (Day −1). Etravirine was 24% higher and 16% lower with atazanavir/ritonavir 300/100 or 400/100 mg qd, respectively, versus historical controls. At Week 48, no significant differences were seen between the atazanavir/ritonavir groups in discontinuations due to adverse events (9.1% each group) and other safety parameters, the proportion of patients with viral load <50 copies/mL (intent-to-treat population, noncompleter = failure) (50.0%, atazanavir/ritonavir 300/100 mg qd versus 45.5%, 400/100 mg qd), and virologic failures (31.8% versus 27.3%, resp.). Conclusions. Etravirine 200 mg bid can be combined with atazanavir/ritonavir 300/100 mg qd and an NRTI in HIV-1-infected, treatment-experienced patients without dose adjustment.
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Etravirine in treatment experienced hiv 1 infected children and adolescents 48 week safety efficacy and resistance analysis of the phase ii piano study
Hiv Medicine, 2014Co-Authors: Gareth Tudorwilliams, Thomas N Kakuda, Steven Nijs, Pedro Cahn, Kulkanya Chokephaibulkit, Jan Fourie, C Karatzios, S Dincq, Magda Opsomer, Lotke TambuyzerAbstract:ObjectivesPIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of Etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (6 to 95%, male sex, low baseline Etravirine weighted genotypic score and high Etravirine trough concentration (C-0h). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were >95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean Etravirine area under the plasma concentration-time curve over 12h (AUC(0-12h); 5216ng h/mL) and C-0h (346ng/mL) were comparable to adult target values. ConclusionsResults with Etravirine 5.2mg/kg bid (with OBR) in this treatment-experienced paediatric population and Etravirine 200mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients
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pharmacokinetic interaction between Etravirine or rilpivirine and telaprevir in healthy volunteers a randomized two way crossover trial
The Journal of Clinical Pharmacology, 2014Co-Authors: Thomas N Kakuda, Steven Nijs, Lorant Leopold, Herta Crauwels, Ann Vandevoorde, Kirk Bertelsen, Marita Stevens, J Witek, Yvon Van Delft, Frank TomakaAbstract:Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or Etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive Etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals. Telaprevir minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the concentration–time curve (AUC) decreased 25%, 10%, and 16%, respectively, when coadministered with Etravirine and 11%, 3%, and 5%, respectively, when coadministered with rilpivirine. Telaprevir did not affect Etravirine pharmacokinetics, but increased rilpivirine Cmin, Cmax, and AUC by 93%, 49%, and 78%, respectively. Both combinations were generally well tolerated. The small decrease in telaprevir exposure when coadministered with Etravirine is unlikely to be clinically relevant. The interaction between telaprevir and rilpivirine is not likely to be clinically relevant under most circumstances. No dose adjustments are deemed necessary when they are coadministered.
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Pharmacokinetics and Short-Term Safety of Etravirine in Combination With Fluconazole or Voriconazole in HIV-Negative Volunteers
The Journal of Clinical Pharmacology, 2013Co-Authors: Thomas N Kakuda, Steven Nijs, James Witek, Goedele De Smedt, Rodica Van Solingen-ristea, Fatima Aharchi, Veerle Vyncke, Richard M. W. HoetelmansAbstract:The nonnucleoside reverse transcriptase inhibitor Etravirine, approved for use in treatment-experienced, HIV-1-infected patients, is a substrate and inducer of cytochrome P450 (CYP) 3A4 and a substrate and inhibitor of CYP2C9/CYP2C19. Pharmacokinetic interactions and safety of Etravirine 200 mg twice daily coadministered with fluconazole 200 mg daily or voriconazole 200 mg twice daily, both inhibitors of CYP3A4, CYP2C9, and CYP2C19, were evaluated in an open-label, randomized, 3-period crossover trial in 18 HIV-negative volunteers. Based on least squares means (LSM) ratios, coadministration of Etravirine with fluconazole or voriconazole resulted in higher Etravirine exposures (area under plasma concentration-time curve from 0-12 hours [AUC12 h] 1.86- and 1.36-fold, respectively). Fluconazole pharmacokinetics were unchanged with Etravirine coadministration (AUC12 h LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC12 h LSM ratio: 1.14). All treatments and combinations were well tolerated, with no grade 3 or 4 adverse events observed during treatment. There was 1 adverse event–related trial withdrawal during treatment with fluconazole alone (leukocyturia). The most frequent adverse events were headache and blurred vision (11 and 8 volunteers, respectively), with blurred vision occurring exclusively during voriconazole-alone treatment. Pharmacokinetic interactions between Etravirine and fluconazole or voriconazole are not expected to be clinically relevant; no dose adjustments are required during coadministration.
Richard M. W. Hoetelmans - One of the best experts on this subject based on the ideXlab platform.
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The effect of single‐ and multiple‐dose Etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects
The Journal of Clinical Pharmacology, 2013Co-Authors: Thomas N Kakuda, Goedele De Smedt, Rodica Van Solingen-ristea, Joelle Onkelinx, Tanja Stevens, Fatima Aharchi, M. Peeters, Lorant Leopold, Richard M. W. HoetelmansAbstract:The effect of Etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of Etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, Etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, Etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + Etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0–8h was slightly increased with Etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that Etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.
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Pharmacokinetics and Short-Term Safety of Etravirine in Combination With Fluconazole or Voriconazole in HIV-Negative Volunteers
The Journal of Clinical Pharmacology, 2013Co-Authors: Thomas N Kakuda, Steven Nijs, James Witek, Goedele De Smedt, Rodica Van Solingen-ristea, Fatima Aharchi, Veerle Vyncke, Richard M. W. HoetelmansAbstract:The nonnucleoside reverse transcriptase inhibitor Etravirine, approved for use in treatment-experienced, HIV-1-infected patients, is a substrate and inducer of cytochrome P450 (CYP) 3A4 and a substrate and inhibitor of CYP2C9/CYP2C19. Pharmacokinetic interactions and safety of Etravirine 200 mg twice daily coadministered with fluconazole 200 mg daily or voriconazole 200 mg twice daily, both inhibitors of CYP3A4, CYP2C9, and CYP2C19, were evaluated in an open-label, randomized, 3-period crossover trial in 18 HIV-negative volunteers. Based on least squares means (LSM) ratios, coadministration of Etravirine with fluconazole or voriconazole resulted in higher Etravirine exposures (area under plasma concentration-time curve from 0-12 hours [AUC12 h] 1.86- and 1.36-fold, respectively). Fluconazole pharmacokinetics were unchanged with Etravirine coadministration (AUC12 h LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC12 h LSM ratio: 1.14). All treatments and combinations were well tolerated, with no grade 3 or 4 adverse events observed during treatment. There was 1 adverse event–related trial withdrawal during treatment with fluconazole alone (leukocyturia). The most frequent adverse events were headache and blurred vision (11 and 8 volunteers, respectively), with blurred vision occurring exclusively during voriconazole-alone treatment. Pharmacokinetic interactions between Etravirine and fluconazole or voriconazole are not expected to be clinically relevant; no dose adjustments are required during coadministration.
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Pharmacokinetic Interactions between Etravirine and Non-Antiretroviral Drugs
Clinical Pharmacokinetics, 2011Co-Authors: Thomas N Kakuda, Monika Schöller-gyüre, Richard M. W. HoetelmansAbstract:Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etra virine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo , Etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between Etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of Etravirine were of no clinical relevance. Likewise, Etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between Etravirine and azithromycin or ribavirin, therefore, Etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased Etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving Etravirine and fluconazole during clinical trials, therefore, Etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with Etravirine. No dose adjustments of digoxin are needed when used in combination with Etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with Etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to Etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with Etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered Etravirine may occur. When co-administered with Etravirine, a dose reduction or alternative to diazepam is recommended. When combining Etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering Etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Coadministration of Etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John’s wort ( Hypericum perforatum ) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease Etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show Etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of Etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.
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clinical perspective on antiretroviral drug drug interactions with the non nucleoside reverse transcriptase inhibitor Etravirine
Antiviral Therapy, 2010Co-Authors: Thomas N Kakuda, Monika Schollergyure, Richard M. W. HoetelmansAbstract:Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with Etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although Etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that Etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to Etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, Etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles.
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Clinical Pharmacokinetics and Pharmacodynamics of Etravirine
Clinical Pharmacokinetics, 2009Co-Authors: Monika Schöller-gyüre, Thomas N Kakuda, Goedele De Smedt, Araz Raoof, Richard M. W. HoetelmansAbstract:Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of Etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, Etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and α_1-acid glycoprotein and shows a relatively long elimination half-life of 30–40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of Etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of Etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of Etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of Etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of Etravirine.
Johan Vingerhoets - One of the best experts on this subject based on the ideXlab platform.
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Virological response with fully active Etravirine: Pooled results from the DUET-1 and DUET-2 trials
International Journal of Std & Aids, 2020Co-Authors: Nathan Clumeck, Steven Nijs, Johan Vingerhoets, Pedro Cahn, Jean-michel Molina, Anthony A. Mills, James WitekAbstract:The objective of this subanalysis of the Phase III DUET trials was to examine virological response to an Etravirine-containing regimen in patients harbouring virus fully sensitive to Etravirine. Full Etravirine sensitivity was defined as fold change in 50% effective concentration (FC) ≤3 or weighted genotypic score ≤2. At Week 48 in the Etravirine group, 74% of patients with Etravirine FC ≤3 and 77% with Etravirine genotypic score ≤2 had viral load
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effect of mutations at position e138 in hiv 1 reverse transcriptase on phenotypic susceptibility and virologic response to Etravirine
Journal of Acquired Immune Deficiency Syndromes, 2011Co-Authors: Lotke Tambuyzer, Steven Nijs, Gaston Picchio, Bjorn Daems, Johan VingerhoetsAbstract:Abstract: The contribution of E138 mutations to Etravirine resistance was investigated. Amino acids at position E138 after failure with Etravirine in DUET were A (n = 1), G (n = 5), K (n = 3), P (n = 1), Q (n = 5), and V (n = 2). At baseline, only E138A and Q were found at 3.0% and 2.5%, respectively. Virologic response (less than 50 copies/mL) was observed in six of 12 and eight of 10 patients with E138A and E138Q, respectively. Site-directed mutants harboring E138A/G/K/Q/R or S showed Etravirine fold change values of 2.9, 2.4, 2.6, 3.0, 3.6, and 2.8, respectively. E138G, K, and Q were added to the existing Etravirine-weighted genotypic score including 17 Etravirine resistance-associated mutations.
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connection domain mutations in hiv 1 reverse transcriptase do not impact Etravirine susceptibility and virologic responses to Etravirine containing regimens
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Soumi Gupta, Steven Nijs, Johan Vingerhoets, Lotke Tambuyzer, Hilde Azijn, Signe Fransen, Arne Frantzell, Roger Paredes, Eoin Coakley, Bonaventura ClotetAbstract:Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on susceptibility and virologic responses to Etravirine were analyzed. Seventeen CDMs were evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, and E399G. CDM prevalence and effects on virologic responses were analyzed retrospectively using clinical data. The effects on Etravirine susceptibility were assessed in clinical samples and confirmed using site-directed mutants. The most prevalent CDMs (>10%) were A371V, E399D, A376S, N348I, A360T, G333E, and L283I. CDM presence was positively correlated with thymidine analogue-associated mutations, but not with NNRTI resistance-associated mutations (RAMs). The presence or number of CDMs did not significantly reduce Etravirine susceptibility, although small reductions were seen in samples with G333D, N348I, A360V, T369I, and A376S. N348I, E399G, and N348I/T369I were associated with reduced Etravirine susceptibility when present with K103N, L100I, or Y181C. N348I or T369I was associated with reduced Etravirine susceptibility when present with K101P or K103R/V179D. Virologic responses to an Etravirine-containing regimen were slightly diminished when G333D, G335D, or A376S was present, but this was not confirmed in subgroups with higher baseline resistance or without Etravirine RAMs. CDMs alone do not confer substantial reductions in Etravirine susceptibility but can further reduce Etravirine susceptibility in combination with certain NNRTI mutations. Since virologic responses to Etravirine were not affected by CDMs, the clinical impacts of these mutations on Etravirine susceptibility appear to be minimal.
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a comparison of neuropsychiatric adverse events during 12 weeks of treatment with Etravirine and efavirenz in a treatment naive hiv 1 infected population
AIDS, 2011Co-Authors: Mark Nelson, Johan Vingerhoets, Andrew Hill, Brian Gazzard, Yvon Van Delft, Hans Jurgen Stellbrink, D Podzamczer, Denes Banhegyi, Thomas Stark, Stephan MarksAbstract:Background: Although efavirenz is a universally recommended treatment for naive HIV-infected individuals, neuropsychiatric adverse events are common. Methods: The Study of Efavirenz NeuropSychiatric Events versus Etravirine (SENSE) trial is a double-blind, placebo-controlled study in which 157 treatment-naive individuals with HIV-RNA higher than 5000 copies/ml were randomized to Etravirine 400 mg once daily (n ¼ 79) or to efavirenz 600 mg once daily (n ¼ 78), with two investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs). The primary end point was the percentage of patients with grade 1–4 drug-related treatmentemergent neuropsychiatric adverse events up to week 12. Results: The study population were 81% men and 85% whites, with a median age of 36 years, baseline CD4 cell counts of 302 cells/ml and HIV-RNA of 4.8 log10 copies/ml. In the intent-to-treat analysis, 13 of 79 individuals (16.5%) in the Etravirine arm and 36 of 78 individuals (46.2%) in the efavirenz arm showed at least one grade 1–4 drugrelated treatment-emergent neuropsychiatric adverse event (P < 0.001). The number with at least one grade 2–4 drug-related treatment-emergent neuropsychiatric adverse event was four of 79 individuals (5.1%) in the Etravirine arm and 13 of 78 individuals (16.7%) in the efavirenz arm (P ¼ 0.019). The change in HIV-RNA to week 12 was � 2.9 log10 in both treatment arms. The median rise in CD4 cell counts was 146 cells/ml in the Etravirine arm and 121 cells/ml in the efavirenz arm. Conclusions: After 12 weeks, first-line treatment with Etravirine 400 mg once daily with two NRTIs was associated with significantly fewer neuropsychiatric adverse events when compared with efavirenz with two NRTIs. The virological and immunological efficacy profile was similar between the two arms. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:335–340
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characterization of genotypic and phenotypic changes in hiv 1 infected patients with virologic failure on an Etravirine containing regimen in the duet 1 and duet 2 clinical studies
AIDS Research and Human Retroviruses, 2010Co-Authors: Lotke Tambuyzer, Steven Nijs, Johan Vingerhoets, Hilde Azijn, Mariepierre De Bethune, Bjorn Daems, Gaston PicchioAbstract:Abstract The randomized, placebo-controlled Phase III DUET studies enrolled treatment-experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including the emergence of individual reverse transcriptase (RT) mutations, in patients who received the non-nucleoside reverse transcriptase inhibitor (NNRTI) Etravirine and experienced virologic failure by rebound by the time of the Week 96 analysis. Patients received Etravirine 200 mg twice-daily in combination with a background regimen containing darunavir/ritonavir, investigator-selected nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. Virologic failure by rebound occurred in 93 (15.5%) Etravirine-treated patients (compared with 170 [28.1%] placebo-treated patients). Patients experiencing virologic failure had more baseline antiretroviral resistance and lower activity of the background regimen relative to those not experiencing failure. Emergence of NNRTI resistance-associate...
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Modelling-Based Prediction of Clinical Benefits from Etravirine in the TMC125-C223 Trial
Hiv Clinical Trials, 2020Co-Authors: Andrew G. Hill, Howard A Grossman, Cal Cohen, Jeff Nadler, Monika PeetersAbstract:AbstractObjective: To predict the decrease in progression to AIDS or death based on the treatment benefit of Etravirine over active control on CD4 counts and HIV RNA. Method: In the TMC125-C223 trial, treatment–experienced patients (n = 199, baseline median CD4 99 cells/μL, HIV RNA 4.7 log10 copies/mL) received optimized background treatment plus either Etravirine 400 mg bid, Etravirine 800 mg bid, or control. CD4 and HIV RNA data were used to predict progression to AIDS or death with two methods: regression method – data from clinical endpoint trials were used to correlate previous CD4 and HIV RNA treatment benefits with clinical progression; CD4 categorization method – data from the EuroSIDA cohort were used to predict rates of disease progression. Results: At week 48, CD4 counts rose by 49 cells/μL for Etravirine 800 mg bid versus 10 cells/μL for control; HIV RNA fell by –1.0 and –0.14 log10 at week 48 in the two groups. The regression method predicted a 39% comparative reduction in progression to AIDS...
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Original research article Effect of steady-state Etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone ☆,☆☆,★
2020Co-Authors: Monika Schöller-gyüre, Thomas N Kakuda, Monika Peeters, Brian Woodfall, Fatima Aharchi, Kati VandermeulenAbstract:Background: Etravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) active against NNRTI-resistant HIV, is an inducer of CYP3A4 and an inhibitor of CYP2C9/19. Study Design: The effect of Etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone was assessed in 30 HIV-negative females. Following a run-in cycle with ethinylestradiol/norethindrone, the pharmacokinetics of ethinylestradiol and norethindrone was assessed on Day 15 of Cycle 2. Etravirine 200 mg bid was coadministered on Day 1 to Day 15 of Cycle 3, with pharmacokinetic assessments of ethinylestradiol, norethindrone and Etravirine on Day 15. Results: When combined with Etravirine, the least-squares means (LSM) ratios (90% confidence interval) for ethinylestradiol AUC24h, Cmax and Cmin were 1.22 (1.13–1.31), 1.33 (1.21–1.46) and 1.09 (1.01–1.18), respectively, compared to administration alone. LSM ratios for norethindrone parameters were 0.95 (0.90–0.99), 1.05 (0.98–1.12) and 0.78 (0.68–0.90), respectively. Conclusion: These changes are not considered clinically relevant. No loss in contraceptive efficacy is expected when coadministered with Etravirine.
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pharmacokinetics and pharmacodynamics of the non nucleoside reverse transcriptase inhibitor Etravirine in treatment experienced hiv 1 infected patients
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Thomas N Kakuda, Janet R Wade, Eric Snoeck, Monika Schollergyure, Monika Peeters, C Corbett, Steven Nijs, Johan Vingerhoets, L Leopold, G De SmedtAbstract:The pharmacokinetics and pharmacodynamics of the antiretroviral agent Etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive Etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration–time curve at 12 h (AUC12 h) and concentration at 0 h (C0 h) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered Etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to Etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between Etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of Etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response. Clinical Pharmacology & Therapeutics (2010) 88 5, 695–703. doi: 10.1038/clpt.2010.181
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Etravirine in the treatment of HIV-1: a clinical overview for healthcare professionals.
Current HIV Research, 2010Co-Authors: Patrick Yeni, Thomas N Kakuda, Monika Peeters, Johan Vingerhoets, Goedele De Smedt, Anthony Mills, Brian WoodfallAbstract:Current HIV treatment guidelines emphasize the importance of using an active antiretroviral therapy regimen that produces full virologic suppression and immunologic competence, while at the same time providing patients with a favorable safety profile and limited risk for development of drug resistance. Etravirine (TMC125), a recently approved, non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown durable, superior virologic efficacy over placebo in the Phase III, randomized, double-blind DUET trials in 1,203 treatment-experienced, NNRTI-resistant, HIV-1-infected patients. Statistical significance of responses with Etravirine over placebo was maintained through Week 24, 48 and 96, regardless of baseline demographics, baseline disease characteristics or the background regimen used. Etravirine has demonstrated a favorable safety and tolerability profile; the incidence of treatment-emergent adverse events was comparable with placebo in the DUET trials, with the exception of rash. The tolerability profile of Etravirine also appears to be favorable in terms of neuropsychiatric and hepatic side effects. The pharmacokinetic profile of twice-daily Etravirine minimizes the potential for clinically relevant drug-drug interactions and allows for its use in combination with a wide range of other agents. In addition, Etravirine has a high genetic barrier to the development of resistance, further enhancing potential benefit in patients infected with NNRTI-resistant virus. The clinical efficacy and favorable safety profile of Etravirine, together with its pharmacokinetic profile and high genetic barrier to resistance, make it a valuable treatment option for a wide range of treatment-experienced HIV-1-infected patients.
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A review of the safety and tolerability profile of the next-generation NNRTI Etravirine
AIDS Research and Human Retroviruses, 2010Co-Authors: Beatriz Grinsztejn, Goedele De Smedt, Brian Woodfall, Giovanni Di Perri, William J. Towner, Monika PeetersAbstract:Abstract The next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) Etravirine (TMC125) has demonstrated durable virologic efficacy in clinical trials involving >1000 treatment-experienced, NNRTI-resistant, HIV-1-infected patients. In this clinical safety review, we show Etravirine to be well tolerated with a proven safety record. The nature and magnitude of adverse events observed during treatment suggest that Etravirine may offer improved tolerability over existing antiretrovirals, including NNRTIs. Notably, adverse events reported with Etravirine treatment are generally mild to moderate in severity. Rash has been shown to occur with a higher incidence in Etravirine-treated patients versus placebo, but cases are generally mild to moderate, occur within the first few weeks, and resolve with continued use. In addition, the rate of adverse event-related discontinuations is low with Etravirine. In summary, the safety and tolerability profile of Etravirine, combined with its virologic efficacy...