Etravirine (TMC-125) approved in the US

HIV Treat Bull - 2008 January/February;9(1/2):

On 18 January 2008, the Food and Drug Administration (FDA) granted accelerated approval for etravirine 100 mg tablets. [1]

The license indication is for treatment-experienced adult patients with resistance to NNRTIs and other ARVs. The recommended daily dose is 2 x 100mg tablets, twice-daily (400mg/day).

FDA granted this accelerated approval based on 24 week viral load and CD4 data from 1,203 adults in two randomised, double-blind, placebo-controlled trials (DUET-1 and -2 studies) in treatment-experienced adults with NNRTI and PI resistance, which have previously been reported in HTB. [2]

The most common adverse events reported in DUET were rash (16.9%) and nausea (13.9%). In general, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. Patients developing a rash while taking etravirine should contact their doctor.

Rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported. Treatment with etravirine should be discontinued if severe rash develops.

Drug interactions between etravirine and other ARVs include no co-administration with tipranavir/r, fosamprenavir/r, atazanavir/ri, full-dose ritonavir (600 mg bid), protease inhibitors administered without ritonavir, and other NNRTIs. Caution is recommended before coadmisistering etravirine with lopinavir/r.

Full details of these studies are included in the SPC. [3]

Etravirine is an NNRTI that was previously developed under the investigational name TMC-125. Etravirine will be marketed under the trade name Intelence.

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US guidelines released on 29 January 2008, already include etravirine. [4]

Of note, they state ‘etravirine should not be used with 2-NRTIs without additional active agents, especially in patients with pre-treatment NNRTI resistance mutations’. This is due to suboptimal treatment responses seen at one trial site in the Phase II study, where patients had accumulated significant NTRI resistance, and therefore cross resistance to any remaining NRTI backbone.

They also highlight that ‘etravirine is a substrate and inducer of CYP 3A4, aswell as being a substrate and inhibitor of 2C9, and 2C19, with complex drug interaction potential. Based on pharmacokinetic studies, either etravirine or the coadministered antiretroviral’s drug exposure may be significantly affected when used in combination. As a result, etravirine is not recommended to be used with any unboosted PI, ritonavir-boosted atazanavir, fosamprenavir, or tipranavir. [5, 6]

References

1. FDA news release ’FDA approves new HIV drug after priority review: etravirine tablets used in combination with other antiretroviral agents’. 18 January 2008.
http://www.fda.gov/bbs/topics/NEWS/2008/NEW01783.html

2. Selected reports from HIV Treatment Bulletin include: DUET studies clarify antiviral efficacy of etravirine and cross-resistance profile to other NNRTIs
http://www.i-base.info/htb/v8/htb8-8-9/DUET.html
Drug interactions with etravirine (TMC-125)
http://www.i-base.info/htb/v7/htb7-12/tmc125.html
Thirteen NNRTI mutations linked to resistance to etravirine
http://www.i-base.info/htb/v8/htb8-6-7/Thirteen.html
Explanation for failure of TMC-125 (etravirine) in TMC227 study
http://www.i-base.info/htb/v7/htb7-12/Explanation.html

3. Full US prescribing information for etravirine is available at:
http://www.intelence.com

4. DHHS Adult and Adolescent Guidelines, 29 January 2008.
http://aidsinfo.nih.gov/
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

5. bid. (see Table 21 and 23b).

6. HIV-druginteractions.org and Liverpool University interaction table
http://www.hiv-druginteractions.org/new/Uploaded_Attachment/51_Etravirine_Chart.pdf

2008-01-10
IB080901-12

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