/publications/issue/2008/2008-09/2008-09-8686

Rx Product News: Profile: A Closer Look at New FDA Actions: Intelence

Author: Caryn Domenici, RPh; Alka Patel, PharmD; Sarah Sanborn, PharmD Candidate; and Sam Kalaminsky


Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women?s Hospital, Boston, Massachusetts. Ms. Sanborn is a sixth-year PharmD candidate from Massachusetts College of Pharmacy currently on clinical clerkship in the Investigational Drug Service at Brigham and Women?s Hospital. Mr. Kalaminsky is a third-year pharmacy student at Northeastern University in Boston.


Tibotec Therapeutics' Intelence

On January 18, 2008, the FDA granted accelerated approval for Tibotec's Intelence (etravirine tablets), a nonnucleoside reverse transcriptase inhibitor (NNRTI).1 It is approved only for use by treatment-experienced HIV-positive adult patients who also have HIV-1 strains resistant to traditional NNRTIs (efavirenz, nevirapine, delavirdine).1,2

The approval was based on Intelence's 2 clinical trials, DUET-1 and DUET-2. Intelence is the first NNRTI to show antiretroviral activity in HIV-1 patients already resistant to currently available NNRTIs and protease inhibitors (PIs).

Pharmacology/Pharmacokinetics

NNRTIs work by directly binding to reverse transcriptase and changing the catalytic site, thereby blocking DNA- and RNA-dependent DNA polymerase activities. 3 Etravirine is different from traditional NNRTIs, because even people who have resistance mutations to the NNRTI class had virus suppression with the use of etravirine. Most importantly, patients who had the common K103N mutation still responded to etravirine.3

The recommended dose of etravirine is 200 mg (two 100-mg tablets) twice daily. When given in a fasting state, the area under the curve of etravirine was decreased by about 50%; therefore, it is recommended that etravirine be taken following a meal.

It is 99.9% bound to plasma proteins. Etravirine undergoes metabolism through CYP3A4, CYP2C9, and CYP2C19, and it also was found to be an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19.3 Therefore, caution should be exercised when administering etravirine with drugs that induce or inhibit CYP3A4, CYP2C9, and CYP2C19. Etravirine may increase warfarin levels; therefore, international normalized ratios should be monitored. Etravirine absorption is not affected by ranitidine or omeprazole. Renal clearance was very small (<1.2%), so no dose adjustments are necessary for patients with renal impairment.3

Clinical Trials

Phase 3 clinical trials DUET-1 and DUET-2, both identical in design, were randomized, double- blind, placebo-controlled trials that included similar patient demographics across the 2 arms: the study arm was etravirine-positive background regimen, and the control arm was placebo-positive background regimen (background regimen consisted of darunavir/ritonavir plus at least 2 other antiretrovirals selected by the investigator).4,5 All subjects had evidence of virologic failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load of >5000 copies/mL, and 3 or more primary PI mutations.

In DUET-1, at week 24, the primary end point of virologic suppression (viral load <50 copies/mL) was seen in 56% (n = 304) of the patients in the etravirine arm, versus 39% (n = 308) in the placebo arm (P=.005). In DUET-2, at week 24, the primary end point of virologic suppression (viral load <50 copies/mL) was seen in 62% (n = 295) of the patients in the etravirine arm, versus 44% (n = 296) in the placebo arm (P = .0003). The most common adverse effects reported in clinical trials were nausea and rash of any type.3

It is important to note that the primary population of these studies consisted of white men who were all very treatment-experienced; this is why the FDA made such a narrow approval for the drug. It still warrants studying in populations such as women, pediatrics, geriatrics, patients with severe liver failure (Class C), treatmentna?ve patients, and other ethnic groups (African Americans, Hispanics, Asians).

Conclusion

The occurrence of AIDSrelated defining illnesses was not statistically significant between the 2 arms at week 24 for either trial, but a combined analysis of both trials showed a statistically significant difference (3.7% of patients had illness in the etravirine arm, vs 6.8% in the control group, P = .02 with a Fisher's exact test).6

Patients should always be genotyped before they start etravirine, because some mutations confer resistance and less virologic suppression. Patients should be advised not to chew or crush the tablets. Interestingly, etravirine tablets are dispersible in water. The patient has to drink it immediately, however, and then rinse the glass several times and drink the rinse in order to get all of the particles

References

  1. FDA Approves INTELENCE (etravirine) for HIV Combination Therapy [press release]. Bridgewater, NJ: Tibotec Therapeutics; January 22, 2008.
  2. Bernard EJ. Etravirine (TMC-125, Intelence) Granted Accelerated Approval in US. www.aidsmap.com/en/news/46E8FC38-3BB8-4DDD-9FEC-D6BFD5DD69AA.asp.
  3. Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics, Division of Ortho Biotech Products LP; 2008.
  4. Madruga JV, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):29-38.
  5. Lazzarin A, Campbell T, Clotet B, et al, on behalf of the DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):39-48.
  6. Hirschel B, Perneger T. No patient left behind--better treatments for resistant HIV infection. Lancet. 2007;370(9581):3-5.