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Etravirine

Author: Paul A. Pham Pharm.D.
04-28-2008

Etravirine not currently available in Zambia

Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

In combination with other ARV agents for the treatment of HIV-1 infection in treatment-experienced pts with PIs, NRTIs, and NNRTI-resistant variants.

NON-FDA APPROVED USES

Potential for use in first-line therapy for pts infected with NNRTI-resistant virus (untested)

FORMS

brand name	preparation	manufacturer	route	form	dosage^	cost*
Intelence	Etravirine (ETR)	Tibotec Pharmaceuticals	Oral	tablet	100 mg	$5.45 per tab

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Pill burden: 4 tabs/day.

ETR 200 mg bid with food
With MVC: MVC 600 mg bid plus ETR 200 mg bid with food.
With MVC + boosted PI: MVC 150 mg bid + ETR 200 mg bid with food.
With DRV/r: DRV/r 600/100mg bid + ETR 200 mg bid with food.
With RAL: RAL 400 mg bid + ETR 200 mg bid with food.
With exception of DRV/r and SQV/r, manufacturer recommends avoiding co-administration or use with caution with other PIs.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

200 mg twice daily

DOSING FOR GLOMERULAR FILTRATION OF 10-50

No data. Usual dose likely since ETR and metabolites are not significantly excreted in urine.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

No data. Usual dose likely since ETR and metabolites are not significantly excreted in urine.

DOSING IN HEMODIALYSIS

No data. Due to high protein binding, ETR is unlikely to be removed in dialysis. Usual dose likely.

DOSING IN PERITONEAL DIALYSIS

No data. Due to high protein binding, ETR is unlikely to be removed in dialysis. Usual dose likely.

DOSING IN HEMOFILTRATION

No data. Due to high protein binding, ETR is unlikely to be removed in dialysis. Usual dose likely.

ADVERSE DRUG REACTIONS

GENERAL

ETR is generally well tolerated.

COMMON

In pts also treated with DRV/r, rash occurred in 17% in ETR treated group vs.9% in placebo-treated pts.
In general, rash was mild to moderate, occurred in 2nd wk and resolved within 1-2 wks on continued therapy. However, 2% required ETR discontinuation. Rash more commonly in women.
Pts with history of NNRTI-related rash did not have higher risk of rash with ETR.

OCCASIONAL

With DRV/r co-administration, moderate to severe (grade 2-4) nausea, abdominal pain, diarrhea, and vomiting reported in approximately 15% of pts comparable to placebo)
Grade of 2 or greater LFTs and bilirubin elevations more common in HBV and HCV co-infected pts.
AST, ALT, and bilirubin elevation occurred in 22.8%, 21.4%, and 5.7%, respectively, vs. 5.5%, 6.1%, and 1.2% of non-co-infected pts treated with ETR.
Fatigue (3.3%)
Peripheral neuropathy (2.8%)
Headache (2.7%)
Hypertension (2.8%)
Total cholesterol elevation (>240 mg/dL) reported in 24% of ETR-treated pts vs. 17% of placebo-treated pnts.
Triglyceride elevation (>500 mg/dL) in 14% of ETR-treated pts vs.11% of placebo-treated pts.
Hyperglycemia (>161 mg/dL) in 16% of ETR-treated pts compared to 13% of placebo-treated pts.

RARE

Severe rash including Stevens-Johnson syndrome and erythema multiforme

DRUG INTERACTIONS

In vitro ETR is CYP3A4, 2C19, and 2C9 substrate. Also undergoes glucuronidation. Not a Pgp substrate. Does not induce or inhibit its own metabolism.
ETR inhibits 2C9 and 2C19
Mild inducer of CYP3A4, 2B6, and glucuronidation in vitro.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Clarithromycin	ETR AUC increased by 42%. Clarithromycin AUC decreased by 39%, but 14-OH-clarithromycin increased by 21%.	Consider azithromycin for MAC treatment. Clinical significance unclear for infections involving S. pneumoniae and H. influenzae since 14-OH-clarithromycin metabolite is active.
Rifampin	ETR's serum concentrations may be significantly decreased	Avoid co-administration
Maraviroc	MVC AUC decreased by 53%. ETR not affected	Increase MVC to 600 mg bid. If a CYP3A4 inhibitor, such as DRV/r, is co-administered with MVC plus ETR, decrease MVC to 150 mg bid.
Atazanavir (ATV)	With unboosted ATV co-administration ETR AUC increased by 50%, but ATV Cmin decreased by 47%.	Avoid unboosted ATV co-administration.
Fosamprenavir/ritonavir (FPV/r)	APV AUC12h, increased by 69%. ETR comparable to historical control.	Unclear clinical significance with FPV/r, but manufacturer recommends avoiding co-administration.
Saquinavir/lopinavir/ritonavir(SQV/LPV/r)	Minor AUC changes in PIs	No dosage adjustments
Saquinavir/ ritonavir (SQV/r)	ETR AUC and Cmin decreased 33% and 29%, respectively. No significant change in SQV AUC.	No dosage adjustments necessary.
Tipranavir/r (TPV/r)	ETR AUC decreased by 76%. TPV and RTV AUC increased by 18% and 23%, respectively.	Avoid co-administration
Darunavir/ritonavir (DRV/r)	DRV AUC increased by 15%. ETR AUC and Cmin decreased by 37% and 49%, respectively.	Despite significant reduction in ETR serum concentrations, good virologic response observed in clinical trials. No dose adjustment necessary.
Didanosine (ddl)	ETR AUC increased 11% (NS). No significant change in ddI AUC.	No dosage adjustments necessary.
Indinavir (IDV)	IDV AUC decreased 46%, ETR AUC increased 51%	Unboosted PIs should be avoided with ETR.
Lopinavir/ritonavir (LPV/r)	LPV AUC decreased 20%(NS), ETR AUC increased 17% (NS)	No dosage adjustments necessary. Unclear clinical significance, but manufacturer recommends co-administration with caution
Ritonavir (RTV 600 mg BID)	ETR AUC decreased 46%	Avoid co-administration with high dose RTV.
Tenofovir (TDF)	ETR AUC decreased by 19%, TDF AUC increased by 15%	No dosage adjustments necessary.
Antiarrhythmics: amiodarone, bepridil, disopyramide, flecainide, lidocaine, mexiletine, propafenone, and quinidine.	Antiarrhythmics serum concentrations may be decreased with ETR co-administration.	Use with caution. Monitor antiarrhythmics serum concentrations.
Anticonvulsants: carbamazepine, phenobarbital, and phenytoin	ETR's serum concentrations may be significantly decreased	Avoid co-administration
Antifungals	All azole antifungals may increase ETVRs serum concentrations. Itraconazole and ketoconazole's serum concentrations may be decreased with ETR co-administration. On the other hand, voriconazole's serum concentrations may be increased. Fluconazole and posaconazole are unlikely to be affected by ETR.	With ETR co-administration, monitor itraconazole and voriconazole serum concentrations. Dose adjustment may be needed.
Atorvastatin	Atorvastatin AUC decreased by 37%. No change in ETR AUC	The dose of atorvastatin may need to be increased.
ATV/r	With ATV/r co-administration ETR AUC increased by 30% and ATV AUC and Cmin decreased by 14% and 38%, respectively.	Unclear clinical significance, but manufacturer recommends avoiding co-administration.
Dexamethasone	ETR serum concentrations may be decreased	Use with caution. Consider an alternative corticosteroid.
Digoxin	Digoxin AUC increased by 18%	Limited data. Consider monitoring digoxin serum concentrations.
Ethinylestradiol and Norethindrone	Ethinylestradiol AUC increased by 22%. Norethindrone AUC decreased by 5%.	Clinical significance unknown. Consider the use of an additional barrier form of contraception.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin, fluvastatin, rosuvastatin and pravastatin	Lovastatin and simvastatin serum concentrations may be decreased. Fluvastatin serum concentrations may be increased. Rosuvastatin and pravastatin are unlikely to be affected with ETR co-administration.	Rosuvastatin and pravastatin may be considered.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	ETR may decrease immunosuppressant serum concentrations.	Monitor serum concentrations of immunosuppressants closely with co-administration.
Methadone	No change in active R(-) methadone	No dosage adjustments necessary
Midazolam	Midazolam AUC decreased by 37%	Limited data. Titrate midazolam to effect. May also decrease triazolam serum concentrations. Lorazepam
NFV	May decrease NFV serum concentrations	Unboosted PIs should be avoided with ETR.
Omeprazole	ETR AUC increased 41% Omeprazole AUC increased 332% (limited data)	No dosage adjustments necessary.
Raltegravir	ETR AUC increased by 10%. No significant change in RAL AUC.	No dosage adjustments necessary.
Ranitidine	ETR AUC decreased 14%	No dosage adjustments necessary.
Rifabutin	ETR AUC and Cmin decreased 37% and 35%, respectively. Rifabutin AUC decreased 17%.	Use standard dose rifabutin 300 mg daily, but avoid co-administration with DRV/r or SQV/r plus ETR due to potential additive decrease in ETR exposure.
Rifapentine	ETR's serum concentrations may be significantly decreased	Avoid co-administration
Sildenafil	Sildenafil AUC decreased 57%	Titrate sildenafil to effect
St. John's Wort	ETR serum concentrations may be decreased	Avoid co-administration
Warfarin	Warfarin AUC increased by 82%	Limited data. Use with close INR monitoring

RESISTANCE

ETR maintained activity against multiple NNRTI resistance, including K103N and Y181C.
3 or more of following mutations at baseline associated with decreased response to ETR: V90I, A98G, L100I, K101E, K101P, V106I, V179D/F, Y181C/I, Y181V, G190A/s.
Highest level or resistance observed with following combination of mutations: V179F+Y181C (187 fold-change), V179F+Y181I (123 fold-change), or V179F +Y181C+F227C (888 fold-change).
Mutations that developed most commonly in subjects with virologic failure were V179F, V179I, Y181C, and Y181I.
Mutations associated with reduction in susceptibility of >3-fold were K101A/P/Q, E138G/Q/C/I/T/V, and M230L. Of these, Y181I and Y181V resulted in the greatest reduction in susceptibility (13 and17-fold, respectively).

PHARMACOLOGY

PHARMACOKINETIC PARAMETERS

Absorption: Absolute bioavailability unknown.
Metabolism and Excretion: ETR undergoes oxidative metabolism by CYP3A4, CYP2C9, and CYP2C19 in vitro. ETR's methylhydroxylated metabolites have 90% less activity against wild-type virus compared to ETR. Primarily excreted in the feces with only 1.2% recovered in the urine.
Protein Binding: 99.9%
Cmax, Cmin, and AUC: With DRV/r co-administration: ETR AUC12h (GM+/-SD): 4531 +/- 4543 ng h/m; ETR Cmin (GM+/-SD): 296 +/- 377 ng/mL
T1/2: 41 (+/- 20) hrs
Distribution: Unknown distribution into CSF and genital tract secretion, but presumed to be low.

DOSING FOR GLOMERULAR FILTRATION OF 50-80

DOSING FOR DECREASED HEPATIC FUNCTION

Child-Pugh Class A and B: 200 mg twice daily. Child-Pugh Class C: no data. Use with caution.

PREGNANCY RISK

Category B. No human data. Not teratogenic in animal studies.

BREAST FEEDING COMPATIBILITY

No data. Breast feeding is not recommended in the U.S. in order to avoid post-natal transmission of HIV to the child, who may not yet be infected.

COMMENTS

Pros: Active against most of the EFV- and NVP-resistant HIV strains, generally well tolerated, with higher genetic barrier to resistance compared to EFV and NVP. Cons: bid dosing, rash, and many complex drug interactions.

References

Richard Haubrich, P Cahn, B Grinsztejn, J Lalezari, J Madruga, A Mills, M Peeters, J Vingerhoets, K Iveson, G De Smedt, and on behalf of the DUET-1 study group.; DUET-1: Week-48 Results of a Phase III Randomized Double-blind Trial to Evaluate the Efficacy and Safety of TMC125 vs Placebo in 612 Treatment-experienced HIV-1-infected Patients. ; CROI 2008; February 3-6, 2008; Vol. Abstract 790; pp.
Rating: Important
Comments:Treatment experienced pts with at least 1 NNRTI mutation and at least 3 PI mutations randomized to placebo or ETR (+ DRV/r + OBR). Baseline characteristics (n=599) of pts on ETRBR were: VL= 4.8 log, CD4 99. 2/3 had extensive ARV treatment history (10-15 ARVs) , 69% had ./-2 detectable NNRTI mutations, 62% had >/- 4 primary PI mutations, and only 4% had prior use of DRV/r. Virologic suppression (VL <50) at 48 wks achieved in 61% of pts in the ETR arms compared with 40% in the placebo arms (p<0.0001). Pooled DUET-1 and -2 data found mean -2.25 log reduction in the ETR arm vs. -1.49 log reduction in placebo arm (p<0.0001). mean increase in CD4 from baseline was higher in the ETR arm (98 vs 73, p=0.0006). If ENF was used de novo, 71% of ETR-treated pts and 59% of placebo-treated pts achieved virologic suppression. ETR was generally well tolerated with rash occurring in 22% and 17% (DUET-1 and -2, respectively) in ETR group vs. only 11% in placebo group. However, rash led to discontinuation in only 2% of ETR-treated pts.
Margaret Johnson, T Campbell, B Clotet, C Katlama, A Lazzarin, W Towner, M Peeters, J Vingerhoets, S Bollen, G De Smedt, and on behalf of the DUET-2 study group.; DUET-2: Week-48 Results of a Phase III Randomized Double-blind Trial to Evaluate the Efficacy and Safety of TMC125 vs Placebo in 591 Treatment-experienced HIV-1-infected Patients. ; CROI 2008; February 3-6, 2008; Vol. Abstract 791; pp.
Rating: Important
Comments:48-wk results of DUET-2