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

Ms. Domenici and Dr. Patel are bothpharmacists at Brigham and Women?sHospital, Boston, Massachusetts. Ms.Sanborn is a sixth-year PharmD candidatefrom Massachusetts College ofPharmacy currently on clinical clerkshipin the Investigational Drug Serviceat Brigham and Women?s Hospital. Mr.Kalaminsky is a third-year pharmacystudent at Northeastern University inBoston.

Tibotec Therapeutics' Intelence

On January 18, 2008, the FDA grantedaccelerated approval for Tibotec'sIntelence (etravirine tablets), a nonnucleosidereverse transcriptase inhibitor(NNRTI).¹ It is approved only for use bytreatment-experienced HIV-positive adultpatients who also have HIV-1 strainsresistant to traditional NNRTIs (efavirenz,nevirapine, delavirdine).^1,2

The approval was based on Intelence's2 clinical trials, DUET-1 and DUET-2.Intelence is the first NNRTI to showantiretroviral activity in HIV-1 patientsalready resistant to currently availableNNRTIs and protease inhibitors (PIs).

Pharmacology/Pharmacokinetics

NNRTIs work by directly binding toreverse transcriptase and changing thecatalytic site, thereby blocking DNA- andRNA-dependent DNA polymerase activities.3 Etravirine is different from traditionalNNRTIs, because even people whohave resistance mutations to the NNRTIclass had virus suppression with the useof etravirine. Most importantly, patientswho had the common K103N mutationstill responded to etravirine.³

The recommended dose of etravirineis 200 mg (two 100-mg tablets) twicedaily. When given in a fasting state, thearea under the curve of etravirine wasdecreased by about 50%; therefore, it isrecommended that etravirine be takenfollowing a meal.

It is 99.9% bound to plasma proteins.Etravirine undergoes metabolismthrough CYP3A4, CYP2C9, and CYP2C19,and it also was found to be an inducerof CYP3A4 and an inhibitor of CYP2C9and CYP2C19.³ Therefore, cautionshould be exercised when administeringetravirine with drugs that induce orinhibit CYP3A4, CYP2C9, and CYP2C19.Etravirine may increase warfarin levels;therefore, internationalnormalized ratios should bemonitored. Etravirine absorptionis not affected by ranitidineor omeprazole. Renalclearance was very small(<1.2%), so no dose adjustmentsare necessaryfor patients with renalimpairment.³

Clinical Trials

Phase 3 clinical trialsDUET-1 and DUET-2,both identical in design,were randomized, double-blind, placebo-controlledtrials that includedsimilar patient demographicsacross the 2arms: the study arm wasetravirine-positive background regimen,and the control arm was placebo-positivebackground regimen (backgroundregimen consisted of darunavir/ritonavirplus at least 2 other antiretroviralsselected by the investigator).^4,5 All subjectshad evidence of virologic failure onstable antiretroviraltherapy, documentedgenotypic evidence of NNRTI resistance,viral load of >5000 copies/mL, and3 or more primary PI mutations.

In DUET-1, at week 24, the primaryend point of virologic suppression (viralload <50 copies/mL) was seen in 56%(n = 304) of the patients in the etravirinearm, versus 39% (n = 308) in the placeboarm (P=.005). In DUET-2, at week 24, theprimary end point of virologic suppression(viral load <50 copies/mL) was seenin 62% (n = 295) of the patients in theetravirine arm, versus 44% (n = 296) in theplacebo arm (P = .0003). The most commonadverse effects reported in clinicaltrials were nausea and rash of any type.³

It is important to note that the primarypopulation of these studies consistedof white men who were all verytreatment-experienced; this is whythe FDA made such a narrowapproval for the drug. It stillwarrants studying in populationssuch as women, pediatrics,geriatrics, patientswith severe liver failure(Class C), treatmentna?vepatients, and otherethnic groups (AfricanAmericans, Hispanics,Asians).

Conclusion

The occurrence of AIDSrelateddefining illnesseswas not statisticallysignificant between the2 arms at week 24 foreither trial, but a combinedanalysis of both trialsshowed a statisticallysignificant difference (3.7% of patientshad illness in the etravirine arm, vs6.8% in the control group, P = .02 with aFisher's exact test).⁶

Patients should always be genotypedbefore they start etravirine, becausesome mutations confer resistance andless virologic suppression. Patients shouldbe advised not to chew or crush thetablets. Interestingly, etravirine tabletsare dispersible in water. The patient hasto drink it immediately, however, andthen rinse the glass several times anddrink the rinse in order to get all of theparticles

References

• FDA Approves INTELENCE (etravirine) for HIV Combination Therapy [press release]. Bridgewater, NJ: Tibotec Therapeutics; January 22, 2008.
• Bernard EJ. Etravirine (TMC-125, Intelence) Granted Accelerated Approval in US. www.aidsmap.com/en/news/46E8FC38-3BB8-4DDD-9FEC-D6BFD5DD69AA.asp.
• Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics, Division of Ortho Biotech Products LP; 2008.
• 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.
• 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.
• Hirschel B, Perneger T. No patient left behind--better treatments for resistant HIV infection. Lancet. 2007;370(9581):3-5.