Lack of antiviral activity of darunavir against SARS-CoV-2.

OBJECTIVES: Given the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. METHODS: Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for the treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. RESULTS: DRV showed no antiviral activity against SARS-CoV-2 at clinically relevant concentrations (EC50 > 100 µM). Remdesivir, used as a positive control, demonstrated potent antiviral activity (EC50 = 0.38 µM). CONCLUSIONS: Overall, the data do not support the use of DRV for the treatment of COVID-19.

Pharmacokinetic evaluation of the interaction between etravirine and rifabutin or clarithromycin in HIV-negative, healthy volunteers: results from two Phase 1 studies.

OBJECTIVES: Drug-drug interactions between etravirine and rifabutin or clarithromycin were examined in two separate open-label, randomized, two-period, crossover trials in HIV-negative, healthy volunteers. METHODS: Rifabutin study: 16 participants received 300 mg of rifabutin once daily (14 days) and then 800 mg of etravirine twice daily (Phase 2 formulation; 21 days) plus 300 mg of rifabutin once daily (days 8-21). Clarithromycin study: 16 participants received 200 mg of etravirine twice daily (commercial formulation; 8 days) and then 500 mg of clarithromycin twice daily (13 days) plus 200 mg of etravirine twice daily (days 6-13). A 14 day washout period between treatments was mandatory in both studies. Full pharmacokinetic profiles of each drug and safety/tolerability were assessed. RESULTS: Rifabutin decreased etravirine exposure by 37%; etravirine decreased rifabutin and 25-O-desacetyl rifabutin exposure by 17%. Clarithromycin increased etravirine exposure by 42%, whereas etravirine decreased clarithromycin exposure by 39% and increased 14-OH clarithromycin exposure by 21%. No serious adverse events were reported in either trial. CONCLUSIONS: Short-term etravirine coadministration with rifabutin or clarithromycin was well tolerated. Etravirine can be coadministered with 300 mg of rifabutin once daily in the absence of an additional potent cytochrome P450 inducer. No dose adjustments are required upon etravirine/clarithromycin coadministration, but alternatives to clarithromycin are recommended when used for Mycobacterium avium complex prophylaxis or treatment.

Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials.

BACKGROUND: Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials. METHODS: HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis. RESULTS: In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4(+) T-cell count from baseline at week 96 were 128 cells/mm(3) with etravirine versus 86 cells/mm(3) with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period. CONCLUSIONS: Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials.

Impact of the background regimen on virologic response to etravirine: pooled 48-week analysis of DUET-1 and -2.

PURPOSE: This subgroup analysis of the phase 3 DUET trials examined the impact of the background regimen on virologic response to etravirine in treatment-experienced patients. METHODS: Patients received etravirine 200 mg or placebo, both twice daily with a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and optional enfuvirtide. Virologic response at week 48 (viral load <50 HIV-1 RNA copies/mL) was analyzed by the number and activity of background agents. RESULTS: Baseline phenotypic sensitivity score (PSS), enfuvirtide use, darunavir fold change in 50% effective concentration (FC), and number of baseline darunavir resistance-associated mutations (RAMs) were significant predictors of response to etravirine (P < .0001, P = .0018, P < .0001, and P = .0120, respectively). The number of active NRTIs was not a significant predictor of response (P = .0626). The highest response rates in etravirine-treated patients were associated with PSS ≥2, de novo enfuvirtide use, darunavir FC ≤10, ≤1 darunavir RAM, and ≥2 active NRTIs. Virologic response was consistently higher in etravirine-treated patients than placebo-treated patients, regardless of the activity of the background regimen. Response rates according to baseline PSS were 46% to 79% in the etravirine group versus 6% to 75% in the placebo group. CONCLUSION: The results of this subanalysis demonstrate higher virologic response rates with increased activity of the background regimen in both treatment groups, with the highest responses achieved in patients using ≥2 active agents in addition to etravirine.

Etravirine in the treatment of HIV-1: a clinical overview for healthcare professionals.

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.

Etravirine: clinical review of a treatment option for HIV type-1-infected patients with non-nucleoside reverse transcriptase inhibitor resistance.

Despite our progressive understanding of HIV type-1 (HIV-1) infection and the development of a number of antiretroviral agents to delay the onset of AIDS, there remains a need for agents with improved efficacy and safety. In particular, therapy options for treatment-experienced adult patients have been limited by the presence of drug-resistant virus, which often leads to a reduced virological response in these patients. The recently approved non-nucleoside reverse transcriptase inhibitor etravirine has demonstrated durable and superior efficacy over placebo and a favourable tolerability profile in HIV-1-infected, treatment-experienced patients, offering a valuable new therapeutic option. This review examines the clinical development and drug profile of etravirine, placing it in the context of other antiretrovirals available for treatment-experienced patients.

A review of the safety and tolerability profile of the next-generation NNRTI etravirine.

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, suggest that the drug may be a valuable option for treatment-experienced patients with HIV-1 infection.

Effects of hepatic impairment on the steady-state pharmacokinetics of etravirine 200 mg BID: an open-label, multiple-dose, controlled Phase I study in adults.

BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against both wild-type HIV and viruses harboring NNRTI resistance. Etravirine is mainly eliminated via the hepatobiliary route. OBJECTIVES: This study in HIV- patients with mild or moderate hepatic impairment and healthy matched controls was conducted to explore the effects of mild and moderate hepatic impairment on the steady-state pharmacokinetics of etravirine and to provide guidance for the treatment of HIV+ patients with hepatic impairment. METHODS: This open-label, multiple-dose study enrolled HIV- patients aged 18 to 65 years with mild or moderate hepatic impairment (Child-Pugh score, 5-6 or 7-9, respectively) and healthy volunteers matched for age, sex, race, and body mass index (BMI). All subjects received etravirine 200 mg BID with food for 7 days and a morning dose on day 8. Etravirine pharmacokinetics over a period of 12 hours on days 1 and 8 were determined using noncompartmental methods and analyzed using linear mixed-effects modeling. Tolerability of etravirine was assessed based on the reported adverse events, laboratory investigations, ECG, and physical examination. RESULTS: Each group comprised 8 subjects (mild hepatic impairment patients: 5 men, 3 women; median age, 57 years [range, 41-65 years]; BMI, 26 kg/m(2) [range, 20-32 kg/m(2)]; moderate hepatic impairment patients: 6 men, 2 women; age, 54 years [range, 44-64 years]; BMI, 26 kg/m(2) [range, 22-32 kg/m(2)]). All patients were white and light smokers. On day 8, the least squares mean ratios (90% CIs) of the log transformed pharmacokinetic properties in patients with mild and moderate hepatic impairment were, respectively: C(min), 0.87 (0.65-1.17) and 0.98 (0.68-1.42) microg/mL; C(max), 0.79 (0.63-1.00) and 0.72 (0.54-0.96) ug/mL; and AUC(0-12), 0.87 (0.69-1.09) and 0.82 (0.60-1.11) microg/mL/h. All treatment-emergent adverse events were considered mild to moderate; the most common were headache (50% in healthy controls) and fatigue and nausea (both 25% in patients with mild hepatic impairment). No clinically significant changes in laboratory parameters, physical examination including vital signs, or ECG were observed. One serious adverse event was reported during the follow-up period in a patient with moderate hepatic impairment due to hepatic cirrhosis secondary to alcoholism. This patient presented at screening with dilated cardiomyopathy and cardiac arrhythmia. CONCLUSIONS: In this Phase I pharmacokinetic study, no clinically relevant differences were observed between patients with mild or moderate hepatic impairment and healthy matched subjects with regard to the pharmacokinetics of etravirine. Based on these findings in these HIV- volunteers, no dose adjustment of etravirine appears to be necessary in patients with mild or moderate hepatic impairment. Etravirine was generally well tolerated.

Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies.

OBJECTIVE: To refine the genotypic and phenotypic correlates of response to the nonnucleoside reverse transcriptase inhibitor etravirine. DESIGN: Initial analyses identified 13 etravirine resistance-associated mutations (RAMs) and clinical cutoffs (CCOs) for etravirine. A multivariate analysis was performed to refine the initial etravirine RAM list and improve the predictive value of genotypic resistance testing with regard to virologic response and relationship to phenotypic data. METHODS: Week 24 data were pooled from the phase III studies with TMC125 to Demonstrate Undetectable viral load in patients Experienced with ARV Therapy (DUET). The effect of baseline resistance to etravirine on virologic response (<50 HIV-1 RNA copies/ml) was studied in patients not using de-novo enfuvirtide and excluding discontinuations for reasons other than virologic failure (n = 406). Clinical cutoffs for etravirine were established by analysis of covariance models and sliding fold change in 50% effective concentration (EC50) windows (Antivirogram; Virco BVBA, Mechelen, Belgium). Etravirine RAMs were identified as those associated with decreased virologic response/increased etravirine fold change in EC50. Relative weight factors were assigned to the etravirine RAMs using random forest and linear modeling techniques. RESULTS: Baseline etravirine fold change in EC50 predicted virologic response at week 24, with lower and preliminary upper clinical cutoffs of 3.0 and 13.0, respectively. A fold change in EC50 value above which etravirine provided little or no additional efficacy benefit could not be established. Seventeen etravirine RAMs were identified and attributed a relative weight factor accounting for the differential impact on etravirine fold change in EC50. Virologic response was a function of etravirine-weighted genotypic score. CONCLUSION: The weighted genotypic scoring algorithm optimizes resistance interpretations for etravirine and guides treatment decisions regarding its use in treatment-experienced patients.

Short-term randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy.

BACKGROUND: In vitro, TMC278, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown activity against wild-type and NNRTI-resistant HIV type-1 (HIV-1) and a higher genetic barrier to the development of resistance than efavirenz or nevirapine. This Phase II open-label trial evaluated the short-term (7-day) antiviral activity of TMC278 administered at three different doses replacing either the protease inhibitor (PI) or NNRTI of an ongoing failing treatment regimen in HIV-1-infected patients. METHODS: A total of 36 patients on failing antiretroviral therapy containing either an NNRTI or a PI (with evidence of > or =1 NNRTI resistance-associated mutation at screening for the PI group) and plasma viral load (VL)>1,000 copies/ml were randomized to one of three once-daily TMC278 doses (25 mg, 50 mg or 150 mg) for 7 days, while continuing NRTIs used at screening. The primary efficacy parameter was the change on day 8 in log(10) plasma VL from baseline. RESULTS: On day 8, median (min, max) changes from baseline in plasma VL were -0.87 (-2.3, 0.0), -0.95 (-1.8, 0.4) and -0.66 (-1.3, -0.2) log(10) copies/ml for the 25 mg, 50 mg and 150 mg once-daily TMC278 groups, respectively (P<0.001-<0.01). Overall, the median change from baseline was -1.19 log(10) copies/ml in the PI-substituted therapy group and -0.71 log(10) copies/ml in the NNRTI-substituted therapy group. TMC278 was generally safe and well tolerated with no apparent differences in safety among the three dose groups. CONCLUSIONS: Once-daily TMC278 showed significant antiviral activity against HIV-1 in treatment-experienced patients with NNRTI failure and/or resistance, and was generally safe and well tolerated.

Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials.

OBJECTIVE: To evaluate the efficacy, safety and virologic resistance profile of etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, over 48 weeks in treatment-experienced adults infected with HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor and other antiretrovirals. DESIGN: DUET-1 (NCT00254046) and DUET-2 (NCT00255099) are two identically designed, randomized, double-blind phase III trials. METHODS: Patients received twice-daily etravirine 200 mg or placebo, each plus a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. Eligible patients had documented nonnucleoside reverse transcriptase inhibitor resistance, at least three primary protease inhibitor mutations at screening and were on a stable but virologically failing regimen for at least 8 weeks, with plasma viral load more than 5000 copies/ml. Pooled 48-week data from the two trials are presented. RESULTS: Patients (1203) were randomized and treated (n = 599, etravirine; n = 604, placebo). Significantly more patients in the etravirine than in the placebo group achieved viral load less than 50 copies/ml at week 48 (61 vs. 40%, respectively; P < 0.0001). Significantly fewer patients in the etravirine group experienced at least one confirmed or probable AIDS-defining illness/death (6 vs. 10%; P = 0.0408). Safety and tolerability in the etravirine group was comparable to the placebo group. Rash was the only adverse event to occur at a significantly higher incidence in the etravirine group (19 vs. 11%, respectively, P < 0.0001), occurring primarily in the second week of treatment. CONCLUSION: At 48 weeks, treatment-experienced patients receiving etravirine plus background regimen had statistically superior and durable virologic responses (viral load less than 50 copies/ml) than those receiving placebo plus background regimen, with comparable tolerability and no new safety signals reported since week 24.

Effect of steady-state etravirine on the pharmacokinetics and pharmacodynamics of ethinylestradiol and norethindrone.

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 AUC(24h), C(max) and C(min) 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.

Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial.

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.

Effects of different meal compositions and fasted state on the oral bioavailability of etravirine.

STUDY OBJECTIVE: To determine the effects of various meal compositions and the fasted state on the pharmacokinetics of etravirine, a nonnucleoside reverse transcriptase inhibitor. DESIGN: Phase I, open-label, randomized, repeated single-dose, three-period crossover trial. SETTING: Clinical pharmacology unit. PARTICIPANTS: Two parallel panels of 12 human immunodeficiency virus (HIV)-negative, healthy, male volunteers. Twenty volunteers completed the study; three withdrew consent, and one was lost to follow-up. Intervention. Panel 1 received a single dose of etravirine 100 mg after a standard breakfast, in the fasted state, and after a light breakfast (croissant). Panel 2 received the same treatment after a standard breakfast, after an enhanced-fiber breakfast, and after a high-fat breakfast. Each treatment was separated by a washout period of at least 14 days. MEASUREMENTS AND MAIN RESULTS: For each treatment, full pharmacokinetic profiles of etravirine were determined up to 96 hours after dosing. Pharmacokinetic parameters were determined by noncompartmental methods and analyzed using a linear mixed-effects model for a crossover design. The least-squares mean ratio for the area under the plasma concentration-time curve from time of administration to the last time point with a measurable concentration after dosing (AUClast) was 0.49 (90% confidence interval [CI] 0.39-0.61) for the fasted state compared with dosing after a standard breakfast. When dosing occurred after a light or enhanced-fiber breakfast, the corresponding values were 0.80 (90% CI 0.69-0.94) and 0.75 (90% CI 0.63-0.90), respectively. When administered after a high-fat breakfast the least-squares mean ratio of AUC(last) was 1.09 (0.84-1.41), compared with dosing after a standard breakfast. Adverse events were also assessed. Under all conditions, single doses of etravirine 100 mg were generally safe and well tolerated. CONCLUSION: Administration of etravirine in a fasted state resulted in 51% lower mean exposure compared with dosing after a standard breakfast. Etravirine should be administered following a meal to improve bioavailability; however, differences in exposure after a standard breakfast versus a high-fat, enhanced-fiber, or light breakfast (croissant) were not considered clinically relevant.

Safety, tolerability, and preliminary efficacy of 48 weeks of etravirine therapy in a phase IIb dose-ranging study involving treatment-experienced patients with HIV-1 infection.

BACKGROUND: Etravirine (ETR; also known as TMC125) is a new nonnucleoside reverse-transcriptase inhibitor with activity against wild-type and nonnucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus type 1 (HIV-1). METHODS: This randomized, phase IIb, placebo-controlled, 2-stage, dose-escalating trial evaluated the safety, tolerability, and preliminary efficacy of 3 twice-daily doses of ETR (experimental formulation TF035; compared with placebo), administered with an individually optimized background regimen, in treatment-experienced HIV-1-infected patients. In stage 1 of the trial, 166 patients received ETR (400 mg or 800 mg twice daily) or placebo. In stage 2 of the trial, 74 patients received ETR (800 mg or 1200 mg twice daily) or placebo. The primary objective was to assess the safety and tolerability of the regimens over 48 weeks. RESULTS: Neuropsychiatric adverse events (AEs) of interest occurred in 46.6% of patients in the combined ETR group and in 45.5% of patients in the combined placebo group (P=.89). Clinically relevant hepatic AEs occurred in 3.4% of patients who received ETR and in 6.1% of patients who received placebo (P=.47), and rash occurred in 19.5% and 12.1%, respectively (P=.25). In general, there was no evidence of a relationship between ETR dose and specific AEs. Most AEs were severity grade 1 or 2; the incidence of grade 3 or 4 AEs was comparable between groups (27.0% in the combined ETR group vs. 27.3% in the placebo group). Plasma preparation tubes were used for viral load measurement. In stage 1, there was no statistically significant difference in efficacy between ETR and placebo. In stage 2, the decrease in log10 plasma viral load between baseline and week 24 was statistically significantly greater in patients who received ETR, compared with patients who received placebo; a trend in favor of ETR persisted until week 48. CONCLUSIONS: ETR was generally safe and well tolerated during long-term administration in treatment-experienced, HIV-1-infected patients, and it had a safety profile comparable to that of placebo.

Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients.

BACKGROUND: An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing. METHODS: Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8. RESULTS: After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (+/-SD) area under the plasma concentration-time curve over 12 h (AUC0-12 h) was 1,284 (+/-958) ng x h/ml when etravirine was administered as 100 mg twice daily (n=33), 3,713 (+/-2,069) ng x h/ml when administered as 200 mg twice daily (n=27) and 2,607 (+/-2,135) ng x h/ml when administered as 800 mg twice daily (n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated. CONCLUSIONS: The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.

A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers.

AIMS: Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS: In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS: Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS: Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.

Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers.

BACKGROUND: Etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, has shown antiviral efficacy in 2 large Phase 3 trials. In vitro and in vivo studies have shown that etravirine is not associated with proarrhythmic potential. Electrocardiograms (ECGs) from healthy and HIV 1-infected volunteers showed no clinically relevant changes. OBJECTIVE: To evaluate the effect of 2 etravirine dosing regimens on QT/corrected QT interval (QTc) in HIV-negative volunteers and assess pharmacokinetic and additional safety parameters. METHODS: A double-blind, double-dummy, randomized, placebo- and active-controlled, 4-period crossover trial was conducted in 41 HIV-negative volunteers. Participants received 4 regimens: etravirine 200 mg twice daily, etravirine 400 mg once daily, moxifloxacin 400 mg once daily (positive control), and placebo in separate 8-day sessions, with each followed by a washout period of 14 or more days. On days -1, 1, and 8 of each session, ECGs were recorded at 11 time points over 12 hours. Pharmacokinetic profiles of etravirine regimens were evaluated and safety was assessed. RESULTS: Thirty-seven subjects completed the study. For etravirine, the upper limit of the 90% CIs of mean time-matched differences in QTc determined using Fridericia's formula (QTcF) was below 10 msec at all time points, the threshold for prolonged QT as defined by regulatory guidelines. The maximum mean (90% CI) difference of time-matched changes in QTcF versus placebo on day 1 was +0.1 msec (-2.6 to 2.9), -0.2 msec (-2.6 to 2.1), and +10.1 msec (7.3 to 12.8) for etravirine 200 mg twice daily, etravirine 400 mg once daily, and moxifloxacin, respectively. On day 8, these values were +0.6 msec (-2.1 to 3.3), -1.0 msec (-4.4 to 2.5), and +10.3 msec (6.8 to 13.9), respectively. Etravirine produced no clinically significant changes in other ECG parameters. No significant differences between males and females were observed. Both etravirine regimens had similar pharmacokinetic exposure and safety profiles. CONCLUSIONS: Etravirine does not prolong the QTc interval. No clinically relevant ECG changes were observed in HIV-negative volunteers. Short-term dosing of etravirine in HIV-negative volunteers was generally safe and well tolerated.

Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers.

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.

Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers.

OBJECTIVE: To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r). DESIGN: Open-label, randomized, two-way crossover Phase I trial. METHODS: Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9-16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively). RESULTS: Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100 mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily. CONCLUSIONS: No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r.