Pharmacokinetics of etravirine with once-daily and twice-daily dosing
Simon Collins, HIV i-Base
A pharmacokinetics and pharmacodynamic analysis from a randomised study of etravirine in treatment-naive patients was published in the May/June edition of Clinical HIV Trials supporting once-daily dosing. 
This was an analysis from a double blind 48-week SENSE trial in 157 treatment-naive patients randomised to either etravirine (4 x 100 mg tablets once-daily with a meal) or efavirenz (600 mg once-daily), plus two NRTIs (tenofovir/FTC – 60%; abacavir/3TC – 26%; and AZT/3TC -14%). The study was designed to compare tolerability of etravirine to efavirenz, with a primary endpoint of CNS events at 12 weeks. Main results from this study – at 12 weeks and 48 weeks – were published in 2011. [2, 3]
Baseline characteristics included 81% male, 85% Caucasian, and median CD4 and viral load at baseline of 302 cells/mm3 and 4.8 log copies/mL (34% were >100,000 copies/mL) respectively.
This secondary analysis looked at the relationship between efficacy, safety and AUC and trough plasma concentrations of etravirine, also in relation to previous PK studies. No significant relationship was observed for either PK parameter and sex, age, body weight or HCV status. Exposure levels were similar to other once-daily studies and higher than 200 mg twice-daily with darunavir/ritonavir plus tenfovoir/FTC, see Table 1.
|Trial||ETR dose||AUC24h (ng*h/mL)||C0h (ng/mL)|
|SENSE trial (n=71)||400 mg QD||12,447 (8,261–15,652)||330 (188–472)|
|HIV 2032 (n=21)||400 mg QD||10,412 (3,364–18,650)||233 (58–480) **|
|Monetra(n=24)||400 mg QD||Not done||422 (264–655)|
|DUET (n=575)||200 mg BD||9,044 (916–119,680)||298 (2–4,852) **|
Note: AUC24h = area under the curve over the dosing interval; C0h = trough concentration; ETR = etravirine; IQR = interquartile range. ** Geometric mean and 95% confidence intervals.
No relationship was reported between any side effects and AUC levels. Data on Cmax was not presented.
Similarly, no relationship was reported for viral load reductions at week 48 (approximately –3.0 for middle quartiles and –3.3 log copies/mL in the lowest and upper quartile) and etravrine trough concentration (<188, 188-329, 330-471 and >471 ng/mL for quartiles 1-4, respectively).
Etravirine has a half-life of 30-40 hours and earlier studies have reported that although trough levels are 25% lower with 400 mg once-daily compared to 200 mg twice-daily dosing, this remains more than 50-fold higher than the protein adjusted IC50 for wild-type HIV (4 ng/mL). [4, 5, 6]
An earlier switch study in treatment-experienced patients reported 3/24 experiencing virological failure although 2 of these 3 were reported to have had etravirine resistance at baseline. 
Several studies have already reported on once-daily etravirine but given the half-life of etravirine is 30-40 hours it is unclear why etravirine was developed as a twice-daily drug.
In this study it is difficult to compare data from once-daily dosing to historical twice-daily studies in combination with darunavir/r which would also have lowered etravirine levels.
Many HIV drugs were approved based on conservative dosing that was later modified to fewer daily doses or reduced dosing – as with AZT, 3TC, d4T, abacavir, nevirapine and efavirenz – but this is dependent on the impact the new dose has on drug levels and supportive evidence in clinical studies. These changes often came long after the initial approval, missing the opportunity of many years of simplified treatment. Raltegravir was a recent exception – perhaps because non-inferiorty to twice daily dosing wasn’t seen because once-daily was used as intial treatment rather than a switch dosing once viral load was suppressed.
- DiPerri G et al. Pharmacokinetics and pharmacodynamics of etravirine 400 mg once daily in treatment naive patients. HIV Clinical Trials, (2013), 14 (3);92-98.
- Nelson M, Stellbrink H, Podzamczer D, et al. A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. AIDS. 2011;25(3):335–340. Concise communication.
- Gazzard B, Duvivier C, Zagler C, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naïve patients: 48-week results. AIDS. 2011;25(18):2249–2258.
- DeJesus E et al. Pharmacokinetics of once-daily etravirine without and with once-daily darunavir/ritonavir in antiretroviral-naïve HIV type-1 infected adults. Antivir Ther. 2010;15:711–720.
- Peter M et al. Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers. Ann Pharmacother. 2008 Jun;42(6):757-65. doi: 10.1345/aph.1K681. Epub 2008 Apr 29.
- Schneider L et al. Switch from etravirine twice daily to once daily in non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-infected patients with suppressed viremia: the Monetra study. HIV Clin Trials. 2012 Sep-Oct;13(5):284-8. doi: 10.1310/hct1305-284.