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Etravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the U.S. Food and Drug Administration in January 2008, is active against many HIV strains that are resistant to first-generation NNRTIs. It is likely to play an important role in the treatment of individuals with NNRTI resistance mutations. Etravirine, however, has therapeutically significant interactions with many other antiretroviral (ARV) drugs, and with other medications, that may substantially affect the efficacy or toxicity of an ARV regimen that contains etravirine. It is important to consider these potential pharmacokinetic interactions when selecting the other agents that will accompany etravirine in the ARV regimen, particularly the protease inhibitors.

Etravirine is a substrate of the cytochrome P450 enzyme system (CYP3A4, CYP2C9, and CYP2C19); it is also an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Etravirine decreases serum concentrations of atazanavir, maraviroc, and raltegravir, and it increases concentrations of fosamprenavir. Etravirine levels are significantly decreased by tipranavir, full-dose ritonavir, efavirenz, and nevirapine. They are modestly decreased by darunavir, saquinavir, and tenofovir, and are increased by lopinavir/ritonavir. These and other interactions are incompletely studied, but based on current information, etravirine should not be given with other NNRTIs, unboosted protease inhibitors, atazanavir/ritonavir, fosamprenavir/ritonavir, or tipranavir/ritonavir. If used with certain other interacting ARVs, dosage adjustment or close monitoring of the patient may be required.

For recommendations on administration of etravirine with other antiretrovirals, see the table below. Note that etravirine also interacts with many nonantiretroviral medications. For information on these, see product label or the HIV InSite Database of Antiretroviral Drug Interactions.

Etravirine Interactions with Other Antiretrovirals

Interacting ARV	Pharmacokinetic Effects	Recommendations and Comments
Abbreviations: AUC = area under the plasma concentration-time curve; BID = twice daily; Cmax = maximal plasma concentration; Cmin = minimal plasma concentration; ETV = etravirine; PI = protease inhibitor Color code: do not coadminister caution may be coadministered; no dosage adjustment required
Nucleoside/Nucleotide Analogues
Didanosine (ddI)	ddI: no significant change in levels ETV: ↑ AUC 11%	Not clinically significant
Tenofovir (TDF)	TDF: ↑ Cmin 19%; ↑ AUC 15%; ↑ Cmax 15% ETV: ↓ Cmin 18%; ↓ AUC 19%	Not thought to be clinically significant
Nonnucleoside Reverse Transcriptase Inhibitors
Delavirdine (DLV)	ETV: anticipate ↑ levels	Do not administer with ETV
Efavirenz (EFV)	EFV: anticipate ↓ levels ETV: ↓ AUC 41%	Do not administer with ETV
Nevirapine (NVP)	NVP: anticipate ↓ levels ETV: ↓ AUC 55%	Do not administer with ETV
Protease Inhibitors (Unboosted)
Atazanavir (ATV)	ATV: ↓ Cmin 47%; ↓ AUC 17% ETV: ↑ Cmin 58%; ↑ AUC 50%; ↑ Cmax 47%	ETV should not be used with unboosted PIs
Fosamprenavir (FPV)	Not studied; significant ↑ in FPV levels expected
Indinavir (IDV)	IDV: ↓ AUC 46% ETV: ↑ AUC 51%
Nelfinavir (NFV)	Not studied; ↑ NFV levels expected
Ritonavir (RTV) (600 mg BID)	ETV: ↓ AUC 46%
Saquinavir (SQV)	SQV: ↓ AUC 52%
Protease Inhibitors (Ritonavir Boosted)
Atazanavir (ATV)-r	ATV: ↓ Cmin 38%; ↓ AUC 14% ETV: ↑ AUC 30%; ↑ Cmax 30%	Do not administer with ETV
Darunavir (DRV)-r	DRV: no significant change in levels ETV: ↓ Cmin 49%; ↓ AUC 37% (ETV 100 mg BID)	Pharmacokinetic studies of ETV 200 mg + DRV-r versus ETV 200 mg alone have not been conducted; it is not known whether dosage adjustment of ETV is necessary In clinical studies, regimens containing DRV-r + ETV were more effective than those containing DRV-r without ETV
Fosamprenavir (FPV)-r	FPV: ↑ Cmin 77%; ↑ AUC 69%; ↑ Cmax 62%	Dosage adjustment not established; do not administer with ETV
Indinavir (IDV)-r	Not studied	Do not administer with ETV
Lopinavir (LPV)-r (Kaletra)	LPV: ↓ Cmin 8%; ↓ AUC 19% ETV: ↑ Cmin 23%; ↑ AUC 17%; ↑ Cmax 15%	No dosage adjustment appears to be necessary
Saquinavir (SQV)-r	SQV: ↓ Cmin 29%; ↓ AUC 37% ETV: ↓ Cmin 29%; ↓ AUC 33%	Clinical significance of decreased SQV and ETV levels is unknown; dosage adjustment not established
Tipiranavir (TPV)-r	TPV: ↑ Cmin 24%; ↑ AUC 18% ETV: ↓ Cmin 82%; ↓ AUC 76%	Do not administer with ETV
Fusion Inhibitors
Enfuvirtide (ENF)	Anticipate no significant change in ENF or ETV levels	No dosage adjustment required
Chemokine Coreceptor Antagonists
Maraviroc (MVC)	MVC: ↓ Cmin 29%; ↓ AUC 53%; ↓ Cmax 60% ETV: no significant change in levels	Dosage adjustment required: ↑ MVC dosage to 600 mg BID (if ETV is given with MVC + DRV-r or other compatible RTV-boosted PI, ↓ MVC dosage to 150 mg BID)
Integrase Inhibitors
Raltegravir (RAL)	RAL: ↓ Cmin 34%; ↓ AUC 10% ETV: no significant change in levels	Clinical significance of decreased RAL levels is not clear; no information available on dosage adjustment

References

Intelence [prescribing information]. Raritan, NJ: Tibotec Therapeutics; January 19, 2008. Available at www.fda.gov/cder/foi/label/2008/022187lbl.pdf. March 1, 2008. Alcorn K. Pfizer Advises Maraviroc Dose Increase if Combined with Etravirine. Aidsmap. London: National AIDS Manual (NAM); July 20, 2007. Accessed Feb. 28, 2008. Baede P, Piscitelli S, Graham N, et al. Drug Interactions with TMC125, a Potent Next Generation NNRTI. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2002; San Diego. Abstract A-1827. Harris M, Zala C, Woodfall B, et al. Pharmacokinetics (PK) and safety of adding TMC125 to stable regimens of saquinavir (SQV), lopinavir (LPV), ritonavir (RTV) and NRTIs in HIV+ adults. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver. Abstract 575b. Kakuda T, Schöller-Gyüre M, Peeters M, et al. Pharmacokinetic interaction study with TMC125 and TMC114/rtv in HIV-negative volunteers. In: Program and abstracts of the XVI International AIDS Society Conference; August 13-18, 2006; Toronto. Abstract TUPE0086. Kakuda T, Schöller-Gyüre M, Woodfall B, et al. TMC125 in combination with other medications: summary of drug-drug interaction studies. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow. Abstract PL5.2. Piscitelli SC, Baede P, Van't Klooster G, et al. TMC125 Does not Alter Lopinavir/Ritonavir (LPV/RTV) Pharmacokinetics in Healthy Volunteers. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2002; San Diego. Abstract A-1824. Scholler M, Kraft M, Hoetelmans R, et al. Significant decrease in TMC125 exposures when co-administered with tipranavir boosted with ritonavir in healthy subjects. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 583. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January 29, 2008. Accessed February 28, 2008.