Pharmacology Update

Etravirine Tablets (Intelence™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved, after priority review, a new non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1 infected adults who have failed other antiretroviral agents. Etravirine (TMC125) has shown in vitro activity against NNRTI-resistant strains. It is marketed by Tibotec Therapeutics, a division of Ortho Biotech Products as Intelence.

Indications

Etravirine is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.1

Dosage

The dose is 200 mg (2 x 100 mg tablets) taken twice daily following a meal.1

Etravirine is available as 100 mg tablets.

Potential Advantage

Etravirine is active in vitro against a large percent (85%) of HIV-1 strains with single amino acid substitution at reverse transcriptase positions associated with NNRTI resistance including the most common (K103N). Overall, etravirine is active against 60% of NNRTI-resistant clinical isolates from clinical trials.1

Potential Disadvantages

Severe and potentially life threatening skin reactions, including Stevens-Johnson syndrome and erythema multiforme have been reported (<0.1%). Etravirine has the potential for numerous drug-drug interactions as it is a substrate of CYP3A4, CYP2C9, and CYP2C19, inhibitor of CYP2C9, and CYP2C19, and inducer of CYP3A4. Coadministration of etravirine with inhibitors, inducers, and substrates of one or more of these isoenzymes may affect the therapeutic effects of etravirine or the coadministered drug. Drugs that should not be coadministered with etravirine include, NNRTIs, protease inhibitors not boosted with ritonavir, tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin, and St John's wort. Etravirine shows decreased susceptibility to mutant HIV-1 strains with 2 or 3 amino acid substitutions. Single substitutions at certain positions (eg, K101, K101Q) show cross-resistance between efavirenz and etravirine.1

Comments

The approval of etravirine was based on the 24-week results of 2 ongoing randomized, double-blind, placebo-controlled, phase 3 studies (TMC125-C206, TMC125-C216 (DUET-1 and DUET-2). Eligible patients included those with documented genotypic evidence of NNRTI-resistance, three or more primary protease inhibitor mutations, viral load over 5000 copies/ml, and on a stable regimen for 8 weeks.1,2,3 All patients received a background regimen containing darunavir/ritonavir and at least 2 investigator selected nucleoside/nucleotide reverse transcriptase inhibitor and optional enfuvirtide. They were randomized to placebo (n = 604) or etravirine at 200 mg twice daily (n = 599).

Primary outcome was proportion of patients with viral load <50 copies/ml. At week 24, 59.8% of those randomized to etravirine had virologic response compared to 40.2% for placebo. Virologic failure rates were 31.7% and 53.0% respectively. There were 9 deaths (1.5%) in the etravirine group and 16 (3.6%) in the placebo group. The discontinuation rates were 7% and 4.1% respectively. Skin and subcutaneous tissue disorders were the most common adverse events (16.9%) with Grade 2 or higher rash (9%). Serious skin reactions (Steven-Johnson syndrome, hypersensitivity reaction, erythema multiforme) have been reported albeit rarely (<0.1%). Etravirine has the potential for numerous drug-drug interactions. The long-term safety and effectiveness of Etravirine is not known. The 30-day wholesale cost for etravirine is $654.

Clinical Implications

Etravirine provides a treatment option for HIV-1 infected patients with NNRTI resistant virus. Due to the potential for multiple drug-drug interactions the combinations of antiretroviral agents that could be used with etravirine is somewhat limited.

References

1. Intelence Product Information. Tibotec Therapeutics. January 2008.

2. Lazzarin A, et al. Lancet. 2007;370:39-48.

3. Madruga JV, et al. Lancet. 2007;29-38.