The Experimental NNRTI Etravirine: An Overview

Etravirine (aka TMC125) is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec that shows potent activity against HIV. In vitro, etravirine has potent activity against both wild-type HIV and NNRTI-resistant variants encoding the L100I, K103N, Y181C, Y188L, and G190A/S mutations.

In September 2006, Tibotec opened an expanded access program (EAP) to provide etravirine to patients in the U.S. who have limited or no treatment options due to virological failure or intolerance to multiple antiretroviral regimens, or who are unable to use currently approved NNRTIs because of resistance or intolerance. The U.S. EAP is part of a larger, international EAP offered by Tibotec. A non-U.S. EAP will be established later in Fall 2006. For detailed information about the U.S. EAP, click here.

Dosing Information

In clinical trials, 100 and 200 mg capsules of etravirine have been tested in dosages of 400, 800, 900, 1200, and 1600 mg twice daily. New tablet formulations have been developed in an effort to increase area under the concentration-time curve (AUC; a measure of serum drug concentration between doses) and Cmax (maximum serum drug concentration) while reducing pill burden.

Pharmacology

Etravirine was designed by Belgian scientists to reduce drug resistance, partly by making a flexible molecule that can fit into the active pocket of HIV's reverse transcriptase in different ways, even when the shape of the pocket changes due to viral mutations that would defeat other drugs. Etravirine has attracted attention because of its activity against NNRTI-resistant strains of HIV.

A new tablet formulation substantially improved the oral bioavailability of etravirine compared with formulations used in previous studies. In the TMC125-C170 trial, all 45 HIV negative participants received 1 reference dose of 400 mg etravirine. After a 2-week washout period, participants received one of 4 test formulations of etravirine.

Etravirine pharmacokinetics were assessed for 96 hours after dosing. Results showed a marked increase in AUC and Cmax for all test formulations compared with the reference dose. Time to maximum serum concentration (Tmax) and elimination half-life (time required to clear half the drug) were similar for all formulations. There was also less pharmacokinetic variability among subjects for the test formulations compared with the reference dose. Treatment with etravirine was generally safe and well tolerated.

Data from Clinical Trials

Several studies of etravirine in HIV positive patients have yielded promising results.

In the TMC125-C207 study, conducted in London, researchers evaluated the efficacy of etravirine in 16 HIV-infected men with documented resistance (10- to 500-fold) to efavirenz (Sustiva/Stocrin). In this open-label, Phase IIa study, treatment with etravirine for 7 days led to a median viral load decrease of slightly less than 10-fold; 7 patients (44%) had a viral load decrease greater than 10-fold. There was no relationship between response to the drug and HIV genotype or phenotype.

In the TMC125-C208 trial, conducted in the Russian Federation in 2001, 12 HIV positive, antiretroviral-naive participants received a 7-day course of etravirine monotherapy at a dosage of 900 mg twice daily; treatment duration was limited to 7 days to prevent the selection of NNRTI-resistant mutants, because rapid emergence of resistance has been observed for first-generation NNRTIs when used as monotherapy. The results from TMC125-C208 were compared with those of the Dutch ERA study (1997-2000), which evaluated the efficacy of a 5-drug, triple-class regimen in treatment-naive individuals with either primary (acute) or chronic HIV infection. The analysis showed that 7 days of etravirine monotherapy produced a decline in viral load similar to that of the 5-drug regimen. The apparent ability of etravirine to substantially reduce HIV viral load in only 7 days suggests that starting treatment with a etravirine-containing regimen might provide superior long-term HIV suppression.

In the TMC125-C223 trial, 199 HIV positive patients were randomly assigned to receive etravirine at either 400 mg or 800 mg twice daily plus an investigator-selected background regimen, or else a standard-of-care regimen. An interim analysis at 24 weeks suggested that etravirine produced viral load reductions of 1.04 log10 for patients receiving 400 mg twice-daily etravirine and 1.18 log10 for those taking 800 mg twice daily, compared with just 0.19 log10 for those on the standard-of-care regimen.

The 48-week analysis showed that HIV viral load decreased by a mean of 0.88 and 1.01 log10 in patients receiving 400 mg and 800 mg twice-daily etravirine, respectively, compared with 0.14 log10 for those in the standard-of-care group. The data indicate that etravirine produced high rates of sustained efficacy in these heavily treatment-experienced patients. Further analysis suggested that etravirine remained active in the presence of multiple NNRTI-resistance mutations.

Highly treatment-experienced patients with drug-resistant HIV may benefit from using etravirine in combination with the recently approved PI darunavir (Prezista). A study of 5 men who started taking 600/100 mg twice-daily darunavir/ritonavir plus 200 mg twice-daily etravirine plus a combination of NRTIs and/or enfuvirtide (T-20; Fuzeon) found that after 4 weeks, etravirine coadministered with darunavir/ritonavir was well tolerated. Interim data showed that viral load decreased, CD4 cell counts increased, and no PI-resistance mutations were observed.

Drug and Food Interactions

A Phase I open-label crossover evaluated drug interactions between etravirine and ritonavir-boosted tipranavir (Aptivus). A total of 24 HIV negative volunteers received 800 mg twice-daily etravirine for 8 days, then stopped taking the drug for a washout period of at least 14 days. After the washout period, subjects were randomly assigned either to:

receive 500/200 mg twice-daily tipranavir/ritonavir for several days, then add 800 mg twice-daily etravirine for the remainder of the study;

receive the same doses of tipranavir/ritonavir plus 800 mg twice-daily etravirine for several days, then stop etravirine for the rest of the study.

Participants took their medications 15 minutes after a meal, and the order of intake was ritonavir, then tipranavir, then etravirine.

When etravirine was co-administered with tipranavir/ritonavir, etravirine exposure (AUC) decreased by 76%, while tipranavir and ritonavir exposures increased 18% and 23%, respectively. Given the clinical relevance of these drug interactions, co-administration of etravirine with tipranavir/ritonavir is not recommended.

In some small studies in HIV negative volunteers, co-administration of 200 mg twice-daily etravirine plus 600/100 mg twice-daily darunavir/ritonavir did not lead to clinically relevant changes in darunavir pharmacokinetics; etravirine concentrations decreased by 37% (as compared with 100 mg twice-daily etravirine), but this reduction is not considered clinically relevant. Serum concentration of darunavir/ritonavir increases when given with 200 mg twice-daily etravirine, at a magnitude greater than when given with 100 mg twice-daily etravirine. This suggests that 200 mg twice-daily etravirine exhibits the best clinical exposure, and this dose was selected for Phase III trials now in progress.

Etravirine has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. In one small open-label study, 16 HIV negative men on stable methadone maintenance therapy received 100 mg twice-daily etravirine for 14 days. No clinically significant withdrawal symptoms were observed, and no dose adjustment of methadone was needed while taking etravirine or during follow-up. Co-administration of etravirine and methadone was generally safe and well tolerated.

The bioavailability of etravirine is not decreased when co-adminstered with the H2-antagonist ranitidine (Zantac) or the proton-pump inhibitor omeprazole (Prilosec); the increase in etravirine exposure when co-adminstered with omeprazole is not considered clinically relevant. In one small, open-label crossover study, 19 HIV negative volunteers were randomly assigned to receive a single dose of 100 mg etravirine alone, 11 days of 150 mg twice-daily ranitidine with a single 100 mg dose of etravirine added on day 8, and 11 days of 40 mg once-daily omeprazole with etravirine added on day 8. Co-administration of a single dose of etravirine with either ranitidine or omeprazole was generally safe and well tolerated.

Adverse Events/Toxicity

In clinical trials to date, etravirine appeared safe and well tolerated. Adverse effects have been mild, and have included headache and diarrhea. In the TMC125-C223 trial, approximately 15% of participants receiving etravirine developed skin rashes, leading several to discontinue therapy.

Clinical Trials
Click here www.ClinicalTrials.gov to search for trials that use etravirine.

Manufacturer Information
Etravirine (TMC125)
Tibotec
1029 Stony Hill Road
Suite 300
Yardley, PA, 19067
609-730-7500

09/22/06

Sources

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