Expanded Drug Access: Etravirine (Formerly TMC-125)

Hopkins HIV Report 2007 Jan; 19(1):8,10

Amanda R. Colquitt, Pharm.D. and Paul A. Pham, Pharm.D.
Johns Hopkins

Manufacturer: Tibotec Pharmaceuticals

Class: Second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI)

Studied Formulations/Storage: 100 mg tablet/store at room temperature

Indication: Treatment of HIV-1 with NNRTI-resistant variants, including those encoding L100I, K103N, Y181C, Y188L, and G190A/S mutations

Expanded access dose: 200 mg twice daily with food (doses up to 1200 mg bid have been evaluated)

Pharmacokinetics:

• AUC_12h: 7,638 ± 2,254 ng*h/mL; C_max: 876 ± 233 ng/mL; C_min: 426 ± 155 ng/mL [Scholler-Gyure M, et al. 46th ICAAC, 2006, Abstract A-371]

• Estimated elimination T1/2: 30-40 hrs [Gruzdev B, et al. AIDS. 2003 Nov 21;17(17):2487-94]

Drug Interactions: In vitro metabolism of etravirine (ETV) is via CYP3A4 and glucuronidation; however, in vivo studies suggest that CYP3A4 is only a minor pathway for etravirine elimination. Etravirine does not induce or inhibit it own metabolism, but appears to be a mild inducer of CYP3A4 [Piscitelli S, et al. 3rd International Workshop on Clinical Pharmacology of HIV Therapy, 2002]. Caution must be used when concomitant use of CYP3A4 substrate medications (see Table on p9).

Clinical data: In an observational study, ten treatment-experienced patients initiating concomitant therapy with DRV/r 600/100 mg bid and ETV 200 mg bid together with two or more NRTIs ± enfuvirtide were evaluated [Boffito M, et al. 46th ICAAC, 2006, Abstract H-1000]. At baseline the median CD4 count was 75 cells/mm³, HIV RNA was 4.67 log₁₀ c/mL, and there was extensive genotypic resistance (7 NRTI mutations, 2 NNRTI mutations, and 4 primary PI mutations). The median viral load decrease was -2.7 log₁₀ c/mL, and the median CD4 increase was 87 cells/mm³. All patients achieved a viral load <400 c/mL; of these, 9 were <40 c/mL. Analysis of a larger prospective, randomized study (DUET) evaluating this combination is in progress.

In a randomized, placebo controlled, partially-blinded study of 199 HIV-infected patients with NNRTI and PI resistance, ETV 400 or 800 mg bid + OBT was compared to the standard of care [Cohen C, et al. Int Conf AIDS. 2006 Aug 13-18;16: Abstract TUPE0061]. At baseline, patients had a median viral load of 4.7 log₁₀ c/mL and a CD4 count of 100 cells/mm³. The mean change in HIV RNA across treatment groups was -0.88 log₁₀ c/mL to -1.01 log₁₀ c/mL compared to -0.14 log₁₀ c/mL in the placebo group. The mean increase in CD4 count was 58-61 cells/mm³ compared to 13 cells/mm³ with control.

Adverse Drug Reactions: ETV is generally well tolerated and comparable to placebo . The most common reported adverse events included diarrhea, rash (mild to moderate), headache, and nausea. Adverse events categorized as grade 3/4 reported by more than 3 patients were hypertriglyceridemia, CPK elevation, and pancreatitis (unclear association) [Montaner J, et al. 10th European AIDS Conference, 2005 Abstract LBPS3/7B]. Of ETV-treated patients, 9% discontinued therapy due to adverse drug events compared to 3% in the placebo group.

Activity: In a retrospective analysis, ETV maintained activity against NNRTI-resistant virus, including virus expressing K103N and Y181C [Vingerhoets J, et al. Antivir Ther. 2006, 11:S22 Abstract 17]. The presence of Y181C in addition to other NNRTI mutations appeared to be associated with higher phenotypic fold-change to ETV; however, there was no significant difference in virologic response at 24 weeks when K103N or Y181C were observed at baseline.

Drug susceptibility assays performed on 2,157 samples revealed 1,081 samples with a ≥10 fold change in EC₅₀ compared to wild- type for at least one of the currently available NNRTIs [Andries K, et al. Antimicrob Agents Chemother. 2004 Dec;48(12):4680-6]. Of these, ETV inhibited 98%.

Resistance: In vitro, mutations selected by ETV varied [Vingerhoets J, et al. J Virol. 2005 Oct;79(20):12773-82]. V179F, Y181C, L214F, and M230L are associated with ETV resistance, especially when present in combination. When ETV is used to treat cells infected with virus expressing the K103N mutation, additional mutations including Y181C/Y with L100I and Y181C with M230M/I were selected. Except for M230L, a fold change of >10 for ETV only occurred in the presence of multiple mutations, such as L100I, K103N, and Y181C (fold change 43). The clinical significance of the observed high barrier to resistance seen in vitro remains to be determined.

Expanded Access Program (EAP): [http://www.tibotec.com/bgdisplay.jhtml? itemname=EAP2_US, Accessed October 17, 2006; http://www.clinicaltrials.gov. Identifier: NCT00354627, Accessed October 11, 2006]

Tibotec Pharmaceuticals has opened its EAP for ETV in the United States. The dose of ETV in this program is 200 mg twice daily with food.

Inclusion Criteria:

• Infected with HIV-1
• ≥18 years old
• Limited or no treatment options due to virological failure or intolerance to multiple ARV regimens
• Unable to use currently approved NNRTIs due to resistance and or intolerance
• Have received licensed oral treatment from each of the 3 major classes of HIV drugs (NRTIs, NNRTIs, PIs)
• • Note for PIs: 2 different PI-based regimens must have been received
  • Note for NNRTI: primary NNRTI resistance can be included if experienced with at least 2 classes of ARVs (PIs, NRTIs) and meet all the other inclusion criteria

Exclusion Criteria:

• Prior or current participation in DUET trials (TMC125-C206 or TMC125-C216)
• Use of concomitant medications prohibited by the protocol
• Use of investigational antiretrovirals (exceptions per protocol)
• Any active, clinically significant disease (i.e. cardiac dysfunction, pancreatitis, acute viral infection) or finding during screening of medical history or physical exam that have not been resolved or stable for ≥30 days before screening phase
• Pregnant or breast-feeding
• Female patient of childbearing potential not using effective non-hormonal birth control
• Patients with specific laboratory abnormalities
• Patients with clinical or laboratory evidence of significantly decreased hepatic function or decompensation

2007-01-10
HHR-2007-01-05

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