Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of human immunodeficiency virus type 1 infection. It is a potent inhibitor of HIV reverse transcriptase and retains activity against wild-type and most NNRTI-resistant HIV. The pharmacokinetic profile of etravirine and clinical data support twice-daily dosing, although once-daily dosing has been investigated in treatment-naive and treatment-experienced persons. Despite similar pharmacokinetic and pharmacodynamic results compared with twice-daily dosing, larger studies are needed to fully support once-daily etravirine dosing in treatment-naive individuals. Etravirine is reserved for use in third- or fourth-line antiretroviral treatment regimens, as recommended, for example, in treatment guidelines by the US Department of Health and Human Services—Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Etravirine exhibits the potential for bi-directional drug–drug interactions with other antiretrovirals and concomitant medications through its interactions with cytochrome P450 (CYP) isozymes: CYP3A4, CYP2C9, and CYP2C19. This review summarizes the pharmacokinetic and pharmacodynamic parameters of etravirine, with particular attention to information on drug–drug interactions and use in special patient populations, including children/adolescents, women, persons with organ dysfunction, and during pregnancy.

Clinical Pharmacokinetics and Pharmacodynamics of Etravirine: An Updated Review.

Anticancer activity profiling of parthenolide analogs generated via P450-mediated chemoenzymatic synthesis.

Introduction: Cobicistat-boosted darunavir is a boosted protease inhibitor in a fixed-dose combination to be approved for the treatment of human immunodeficiency virus type1 infection. It contains darunavir, a well-known protease inhibitor with a good efficacy and safety profile, and the new pharmacokinetic enhancer cobicistat. The convenience of this combination in a single pill makes this compound easier to take, thus improving adherence.Areas covered: PubMed and www.clinicaltrials.gov were searched with the term “darunavir/cobicistat” for all clinical trials conducted up to date, as well as for those ongoing and to be opened in the near future as well as for pharmacology data. A review of abstracts from major infectious diseases (particularly those dedicated to human immunodeficiency disease) and pharmacology conferences from 2010 to 2015 was also conducted.Expert opinion: improving adherence, particularly by minimizing pill burden with convenient formulations (i.e., fixed-dose combination), is one of ...

Darunavir/cobicistat for the treatment of HIV-1: a new era for compact drugs with high genetic barrier to resistance

With the efficacy of antiretroviral therapy already guaranteed for all practical purposes, the main objective in the management of HIV-positive patients has moved to reduce and prevent potential long-term toxicities. Nucleos(t)ide-sparing regimens could enable the best to address this issue, with a wide range of current options that may allow adaptation to distinct patient populations. Monotherapy with boosted darunavir and lopinavir has been safely prescribed as maintenance therapy to stable patients on stable antiretroviral therapy without nadir CD4 count < 200/mm³, low-level baseline viremia, prolonged viral suppression, and without prior virologic failure. In the presence of all these requirements, dual therapy with lamivudine plus boosted lopinavir or atazanavir has been shown to be equivalent to standard triple therapy. Other nucleoside-sparing dual therapies, especially using raltegravir combined with boosted darunavir or lopinavir and etravirine or rilpivirine in combination with boosted darunavir, have performed well as simplification strategies or rescue interventions in a wide spectrum of patients as long as drug resistance was absent. With current economical constrains, nuke-sparing regimens have attained a degree of maturity that makes it possible to anticipate that they will play an important role in the optimization of antiretroviral therapy in the near future.

Nuke-Sparing Regimens for the Long-Term Care of HIV Infection.

Objectives To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice.

Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients

Objectives

Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naive subjects with transmitted resistance.



Methods

In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at week 48 [confirmed virological response (CVR), non-virological failure (VF) censored]. Key secondary endpoints included assessments of changes from baseline to week 48 in viral load, immunological response, pharmacokinetics/pharmacodynamics, safety, tolerability, metabolic and bone markers and body fat.



Results

Forty-one of the 54 enrolled subjects completed the study. Adverse events (7%) and VF (7%) were the most common reasons for discontinuation. The week 48 CVR rate in the intent-to-treat (ITT) non-VF censored population was 89% (primary endpoint). Seven subjects experienced VF. Common adverse events were diarrhoea (15%), rash (15%) and upper respiratory tract infection (11%). Mild/moderate lipid elevations, minimal changes in limb fat distribution and bone mineral density and no clinically relevant changes in glucose metabolism were observed.



Conclusions

Etravirine 400 mg and darunavir/ritonavir 800/100 mg as a two-drug once-daily regimen in treatment-experienced subjects or treatment-naive subjects with transmitted resistance was virologically efficacious and well tolerated.

The Intelence aNd pRezista Once A Day Study (INROADS): a multicentre, single-arm, open-label study of etravirine and darunavir/ritonavir as dual therapy in HIV-1-infected early treatment-experienced subjects.

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The Intelence aNd pRezista Once A Day Study (INROADS): a multicentre, single-arm, open-label study of etravirine and darunavir/ritonavir as dual therapy in HIV-1-infected early treatment-experienced subjects.