Clinical Pharmacokinetics and Pharmacodynamics of Etravirine

Clinical Pharmacokinetics and Pharmacodynamicsof EtravirineMonika Scholler-Gyure,1 Thomas N. Kakuda,2 Araz Raoof,1 Goedele De Smedt1 and Richard M.W. Hoetelmans1

1 Tibotec BVBA, Mechelen, Belgium

2 Tibotec Inc., Yardley, Pennsylvania, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561

1. Biopharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

2.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

2.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

2.3 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563

2.4 Dose and Formulation Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564

2.5 Pharmacokinetics in Healthy Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

2.6 Pharmacokinetics in HIV-Infected Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

2.7 Pharmacokinetics in Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

3. Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

3.1 In Vitro Interaction Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

3.2 In Vivo Interaction Potential. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566

3.2.1 Effect of Etravirine on Coadministered Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

3.2.2 Effect of Coadministered Drugs on Etravirine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

4. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

Abstract Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the

treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, andmaintains

its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in

HIV-infected patients at the recommended dosage of 200mg twice daily demonstratesmoderate intersubject

variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach,

etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin

and a1-acid glycoprotein and shows a relatively long elimination half-life of 30–40 hours. Etravirine is

metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuro-

nidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible.

Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a

mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well

characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or

mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of

etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the

pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the

safety profile of etravirine.

REVIEW ARTICLEClin Pharmacokinet 2009; 48 (9): 561-574

0312-5963/09/0009-0561/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

Etravirine (formerly known as TMC125) is a novel diaryl-

pyrimidine (figure 1) non-nucleoside reverse transcriptase

inhibitor (NNRTI) developed to inhibit NNRTI-resistant

HIV-1. The spectrum of activity of etravirine is attributed to its

ability to bind HIV reverse transcriptase in more than one

distinct mode. The torsional flexibility of the molecule permits

access to numerous conformational variants and its compact

structure allows repositioning and reorientation when muta-

tions in the binding pocket are present. Significant in vitro ac-

tivity and a high genetic barrier to resistance of etravirine was

demonstrated against a panel of viruses with single or double

mutations conferring NNRTI-resistance, including viruses har-

bouring K103N with K101E or Y181C. Unlike first-generation

NNRTIs, resistance to etravirine develops following multiple

mutations in reverse transcriptase.[1,2]

Etravirine is approved in several jurisdictions for use in

combination with other antiretroviral agents for the treatment

of HIV-1 infection in treatment-experienced adult patients.

This article summarizes the pharmacokinetic and pharmaco-

dynamic properties of etravirine.

1. Biopharmaceutics

Etravirine is categorized as a Biopharmaceutics Classification

System Class IV compound (low solubility and permeability). The

compound is highly lipophilic with an octanol ��water partition

coefficient (log P) >5 and an ionization constant pKa

<3, and is virtually insoluble in water. The molecular weight of

etravirine is 435 Da. Solubility has been improved by physical

modifications of the drug substance, in particular by developing

solid dispersion formulationswith etravirine in an amorphous form

homogenously dispersed in a polymer matrix. The currently mar-

keted 100mg tablet formulation is a result of numerous evaluations

of different formulation concepts and demonstrates an acceptable

relative oral bioavailability, drug load and physical stability.[3]

2. Pharmacokinetics

The pharmacokinetics of etravirine have been extensively

studied in healthy subjects and in HIV-infected patients. This

article summarizes pertinent data obtained with the experimental

phase II formulation and the phase III/commercial formulation.

2.1 Absorption

Maximumplasma concentrations are generally reachedwithin

4–5 hours after administration,[4,5] suggesting the proximal

small intestine as the major site of absorption. In vitro studies

conductedwith human colon carcinoma-derived (CACO-2) cells

have not demonstrated transepithelial transport of etravirine

by P-glycoprotein or other efflux transporters expressed on

CACO-2. Intestinal permeability is concentration independent

and occurs predominantly via passive transcellular diffusion.[6]

The presence of food has a significant impact on the oral bio-

availability of etravirine. The effect ofmeals of various composition

has been studied in a repeated single-dose trial in healthy subjects.[7]

Administration of etravirine in the fasted state resulted in 51%lower mean exposure than intake following a standardized break-

fast. In contrast, no significant difference has been observed in the

pharmacokinetics of etravirine when given following a standar-

dized breakfast (561kCal, 15g fat) versus a high-fat breakfast

(1160kCal, 70g fat). Exposure to etravirine after intake following a

croissant (345kCal, 17g fat) or an enhanced-fibre breakfast

(685kCal, 3g fat) was 20% and 25% lower, respectively, than when

taken following a standardized breakfast. These changes in oral

bioavailability might be explained by improved solubilization due

to increased bile contents and the presence of lipid digestion pro-

ducts within the intestinal lumen and prolonged gastric residence

time, enabling dissolution and mixing of etravirine following food

intake. To achieve optimal exposure, it is recommended to ad-

minister etravirine following a meal; however, no clinical relevance

has been attributed to the differences in pharmacokinetics when

etravirine was taken following meals of different composition.

A drug interaction studywith a single dose of etravirine given

with steady-state ranitidine or omeprazole treatment demon-

strated no clinically relevant effect when etravirine was co-

administered with these acid suppressing agents, suggesting that

alterations in pHdo not affect the bioavailability of etravirine.[8]

2.2 Distribution

Etravirine is extensively bound (99.9%) to albumin and

a1-acid glycoprotein, with a blood to plasma concentration ratio

O N NH

N

N N

NH2

Br

Fig. 1. Chemical structure of etravirine.

562 Scholler-Gyure et al.

ª 2009 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2009; 48 (9)

of 0.7.[9] The apparent volume of distribution of etravirine for

the central compartment is 422 L.[5] The distribution of etra-

virine into compartments other than plasma (e.g. cerebrospinal

fluid, genital tract secretions) has notbeen evaluated inhumans, but

due to high protein binding, extensive penetration is not expected.

2.3 Metabolism and Elimination

Etravirine has a relatively long elimination half-life; the

mean terminal elimination half-life of etravirine is 30–40 hours.

Overall, etravirine metabolism is mainly catalysed by cyto-

chrome P450 (CYP) 3A and CYP2C9 and CYP2C19. The

major metabolic pathway of etravirine is methylhydroxylation

of the dimethylbenzonitrile moiety to form monohydroxylated

(metabolite 12) or dihydroxylated (metabolite 8) etravirine[10]

(figure 2). Hydroxylation at a site on the dimethylbenzonitrile

moiety apart from the methyl groups (metabolite 13) occurs to

a minor extent. Glucuronide conjugates of these metabolites

are also formed. Metabolite profiling and identification using

samples obtained in a single-dose mass balance trial confirmed

N

O

N

HN

NH2

Br

C

CN

N

N

O

N

HN

NH2

Br

C

CN

N

Oxidationfaeces

Oxidation faeces and plasma

Etravirine (TMC125)

Metabolite 13

Oxidationurine, faeces and plasmaN

O

N

HN

NH2

BrHO

C

CN

N

N

O

N

HN

NH2

BrHO

C

CN

N

Glucuronidationurine

Metabolite 12

Metabolite 6

⎡⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎣

⎡⎢⎢⎢⎢⎢⎢⎣

⎤⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎦

⎤⎥⎥⎥⎥⎥⎥⎦

Glucuronidation

HO

Glucuronidationurine and plasma

Metabolite 8

Metabolite 1

⎡⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎢⎣

⎤⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎥⎦

Glucuronidation

N

O

N

HN

NH2

BrHO

C

CN

NOH

N

O

N

HN

NH2

BrHO

C

CN

NOH

Fig. 2. Metabolism of etravirine.

Clinical Pharmacology of Etravirine 563


the in vitro results.[11] Most of the etravirine-related radio-

activity was excreted in faeces as unchanged drug. No

unchanged etravirine was detected in the urine. No pharmaco-

logical activity was demonstrated for the metabolites of etra-

virine in the presence of NNRTI-resistant HIV.[12]

2.4 Dose and Formulation Selection

Based on the relatively long elimination half-life, a once-

daily dosing regimen was a plausible option for etravirine ad-

ministration. However, the pill burden of initial formulations

precluded the use of once daily dosing, and ultimately led to the

maintenance of twice daily regimens throughout the entire de-

velopment programme.

In a dose-finding phase II trial, etravirine administered with

an investigator-selected optimized background regimen con-

sisting of at least two antiretrovirals (NRTI or NNRTI and/orlopinavir/ritonavir and/or enfuvirtide) was effective after

48 weeks at both doses of etravirine tested (400mg and 800mg

twice daily of the experimental formulation) compared with a

control group that received at least three investigator-selected

antiretrovirals. Patients receiving 800mg twice daily of etra-

virine showed a 1.01 log10 reduction inHIVRNA, versus a 0.14

log10 reduction in the control group after 48 weeks.[13] Treat-

ment with etravirine was generally safe and well tolerated.[14]

Based on the results of the phase IIb trials, the dose of 800mg

twice daily, i.e. four 200mg tablets of the experimental for-

mulation twice daily was selected.

In parallel with the phase IIb trial, a spray-dried formulation

of etravirine was developed to improve bioavailability and re-

duce pill burden. A comparative multiple dose bioavailability

trial in HIV-infected patients demonstrated that the phase III

solid dispersion formulation at a dosage of 200mg twice daily

provides a pharmacokinetic profile comparable with 800mg

twice daily of the experimental formulation, with reduced in-

terindividual variability. In summary, a dosage of etravirine

200mg twice daily, i.e. two 100mg tablets twice daily of the

solid dispersion formulation, was selected as the dosage for

phase III and all other subsequent trials with etravirine.[15]

A compositionally proportional 25mg tablet formulation

has been developed for paediatric use and is currently being

evaluated in children and adolescents between 6 and 17 years of

age. An alternative possibility for the administration of etra-

virine in children and in adults who experience difficulties with

swallowing is to disperse the tablets prior to administration and

drink the dispersion immediately. A three-period crossover bio-

availability trial in healthy HIV-negative adults demonstrated

no relevant changes in oral bioavailability of etravirine when

administered as four 25mg tablets (whole) or as one 100mg

tablet dispersed in water, compared with one 100mg tablet

swallowed whole.[16] Etravirine dispersed in water is tasteless

and odourless. Etravirine is stable in water at ambient tem-

peratures for up to 6 hours. Of note, liquids other than water

have not been evaluated and therefore are not recommended

for the preparation of etravirine dispersion.

Two multiple-dose trials were conducted to compare the

pharmacokinetics of etravirine given once or twice daily. In

both trials, comparable daily systemic exposures to etravirine

were obtained with once daily and twice daily administration

of the same daily dose (table I). The minimum plasma con-

centration (Cmin) of etravirine was 25–26% lower with the

once daily regimen compared with the twice daily regimen of

the same daily dose; the maximum plasma concentration

(Cmax) was approximately 42–44% higher when given once

Table I. Pharmacokinetic parameters of etravirine in healthy HIV-negative subjects after multiple-dose (8 days) administration of the commercial

formulation[4] a

Parameter Dose

100 mg bid 200 mg od 200 mg bid 400 mg od

No. of subjects 23 24 39 37

tmax [h]b 4.0 (2.0–6.0) 4.0 (2.0–6.0) 4.08 (2.08–6.08) 4.08 (3.08–6.13)

C0 [ng/mL] 234 – 92 167 – 77 530 – 173 382 – 145

Cmax [ng/mL] 471 – 141 659 – 177 959 – 278 1393 – 386

AUC12 [ng�h/mL] 3925 – 1251 8195 – 2428

AUC24 [ng�h/mL] 8054 – 2748 17 220 – 5009

a Values are expressed as mean – SD unless specified otherwise.

b Median (range).

AUC = area under the plasma concentration-time curve; AUC12 = AUC from 0 to 12 hours; AUC24 = AUC from 0 to 24 hours; bid = twice daily; C0 = trough plasma

concentration; Cmax = maximum plasma concentration; od = once daily; tmax = time to reach the Cmax.



daily (figure 3).[4] Etravirine is approved at a dosage of 200mg

twice daily; pharmacokinetic trials to further evaluate once

daily dosing are ongoing.

2.5 Pharmacokinetics in Healthy Subjects

When administered as a single dose or in multiple doses of

the commercial formulation in healthy subjects, the exposure

to etravirine increases dose proportionally across the range

of 100–400mg.[4,17] The rate of absorption of etravirine is

not influenced by the dose. Mean area under the plasma

concentration-time curve (AUC) and Cmax at steady-state

(after 7 days dosing) is approximately 2.5- to 4-fold higher than

after a single dose in a once daily or twice daily regimen,

respectively.[4] A summary of the main pharmacokinetic para-

meters in healthy HIV-negative subjects is given in table I.

Intersubject variability of AUC from 0 to 12 hours (AUC12)

and Cmax at steady-state with 200mg twice daily when ad-

ministered following a meal is approximately 30% (coefficient

of variation [CV]).[4,17,18] Based on data of two pharmacoki-

netic multiple-dose, two-period, crossover trials administering

etravirine following a meal in once daily or twice daily regi-

mens, the intrasubject variability of AUC12 in healthy subjects

is estimated to be <17% (CV) after the first dose and <10% in

steady state.[4]

2.6 Pharmacokinetics in HIV-Infected Patients

A summary of the steady-state pharmacokinetics of etra-

virine in HIV-1 infected patients participating in pharmaco-

kinetic substudies of the phase III trials DUET-1 and DUET-2[5]

is given in table II. Of note, these patients were also treated with

darunavir/ritonavir 600mg/100mg twice daily, a drug known

to interact with etravirine (see section 3). A two-compartmental

model with sequential zero- and first-order absorption includ-

ing lag-time was used to individually estimate AUC12 and

trough concentration (C0). DUET-1 and DUET-2 collectively

enrolled 1203 patients of which 599 were randomized to

etravirine; population pharmacokinetics were estimated in

575 patients. The mean (SD) population-estimated etravirine

AUC12 and C0 were 5506 (4710) ng�h/mL and 393

(391) ng/mL, respectively. Intersubject variability (CV) of the

clearance was 60% and intrasubject variability of the bio-

availability was 40%.

The effect of intrinsic and extrinsic factors (age, bodyweight,

sex, race, hepatitis coinfection status, adherence asmeasured by

pill count, use of enfuvirtide and use of tenofovir disoproxil

fumarate) on the pharmacokinetics of etravirine was also asses-

sed in the DUET trials.[5] The mean (SD) etravirine AUC12 in

57 women was 6027 (3591) ng�h/mL compared with 5449

(4817) ng�h/mL in 518 men (p = 0.20). Mean (–SD) etravirine

in Caucasians (n = 360), Blacks (n = 67), Hispanics (n = 56) and

Asians (n = 7) was 5552 – 5264, 5451 – 3524, 5183 – 2483 and

10 299 – 7185 ng�h/mL, respectively (p = 0.23). Etravirine

exposure (AUC12) increased with increasing adherence

(p = 0.0187) or decreasing bodyweight (p = 0.0490). The use of

0

200

400

600

800

1000

1200

1400

1600

1800

0 4 8 12 16 20 24

Time (h)

Pla

sma

conc

entr

atio

n (n

g/m

L)

Etravirine 400 mg odEtravirine 200 mg bid

Fig. 3. Pharmacokinetic profile of etravirine administered as 400 mg once

daily (od) [n = 37] and 200 mg twice daily (bid) [n = 39] of the commercial

formulation for 8 days in healthy subjects. The data are presented as

mean (SD).

Table II. Pharmacokinetic parameters of etravirine in HIV-1 infected patients after multiple-dose (4 and 24 weeks) administration of the commercial formulation

in the DUET trials[5]

Parameter Week 4 [n = 25] Week 24 [n = 23]

mean – SD median (range) mean – SD median (range)

C0 [ng/mL] 545 – 819 260 (110–3960) 446 – 533 297 (75–2710)

Cmax [ng/mL] 880 – 1030 525 (285–4980) 797 – 668 586 (199–3130)

tmax [h] 4 (0–6) 4 (1–6)

AUC12 [ng�h/mL] 7964 – 11 180 4307 (2284–53 870) 7034 – 7238 5253 (1709–35 570)

AUC12 = area under the plasma concentration-time curve from 0 to 12 hours; C0 = trough plasma concentration; Cmax = maximum plasma concentration;

tmax = time to reach the Cmax.



enfuvirtide had no effect on etravirine exposure (p = 0.80).

Consistent with the results of the phase I drug-drug interaction

studies,[18] the use of tenofovir disoproxil fumarate was asso-

ciated with a 26% decrease in AUC12 (p = 0.0005). Hepatitis B

and/or C co-infection was associated with a 1.35-fold increase

in etravirine exposure (p = 0.0028). There was a trend for higher

etravirine exposure with higher age (p = 0.0645). Because of

the wide therapeutic window for etravirine (see section 4), no

dose adjustments for etravirine are necessary based on these

covariates.

2.7 Pharmacokinetics in Special Populations

The low amount of radioactivity excreted in the urine in the

mass balance study[11] indicated minimal renal elimination of

etravirine and its metabolites. Specific trials to investigate

etravirine pharmacokinetics in subjects with renal impairment

were therefore not conducted. In an open-label, multiple-dose

pharmacokinetic trial conducted in HIV-negative subjects with

mild (Child-Pugh Class A, n= 8) or moderate (Child-Pugh

Class B, n= 8) hepatic impairment and healthy subjects

matched for age (–5 years), sex, race, bodymass index (–15%) and

smoking status (n = 16), no clinically relevant differences were

observed in the pharmacokinetics of etravirine in HIV-negative

subjects with and without liver dysfunction.[19] After 8 days

treatment with etravirine 200mg twice daily the exposure to

etravirine was 13% and 18% lower in patients with mild and

moderate hepatic impairment, respectively, than in healthy

matched controls. No clinically relevant adverse events or

changes in laboratory parameters were observed. Based on the

results of this study, the dose of etravirine in patients with

mild and moderate hepatic impairment does not need to be

modified.

3. Drug-Drug Interactions

3.1 In Vitro Interaction Potential

In a study with etravirine, using human liver microsomes,

inhibition of CYP2C9 has been identified as an effect of po-

tential clinical relevance with an inhibitory constant (Ki) of

0.58 mmol/L (0.25 mg/mL).[20] The more than 10-fold higher Ki

values for other isoenzymes indicated lower affinity. The

potential of etravirine to induce CYP isoenzymes was deter-

mined in human primary hepatocyte cultures, demonstrating

an increase in CYP3A4 activity. The apparent etravirine con-

centration that produces 50% inhibition of P-glycoprotein was

shown to be considerably higher than expected plasma concen-

trations. Based on its metabolism, drugs inhibiting or inducing

CYP2C isoenzymes and CYP3A4 were expected to affect the

pharmacokinetics of etravirine.

3.2 In Vivo Interaction Potential

The in vivo interaction potential of a single dose and steady-

state etravirine was evaluated in a two-period crossover study

in 14 healthy HIV-negative subjects using the modified Coop-

erstown 5 + 1 cocktail (150mg caffeine [CYP1A2], 10mg

warfarin + 10mg vitamin K [CYP2C9], 40mg omeprazole

[CYP2C19], 30mg dextromethorphan [CYP2D6] orally, and

0.025mg/kg midazolam intravenously [CYP3A]).[21,22] After

14 days treatment with 200mg etravirine twice daily the AUC

from time zero to last measured concentration (AUClast) least-

squares mean (LSM) ratios for the cocktail compounds coad-

ministered with etravirine versus given alone were: caffeine 0.85

(90% CI 0.78, 0.91), S-warfarin 1.05 (90% CI 0.93, 1.19),

omeprazole 1.83 (90% CI 0.78, 4.29), dextromethorphan 0.94

(90% CI 0.72, 1.23) and midazolam 0.69 (90% CI 0.64, 0.74).

LSM ratios for the parent/metabolite ratio of AUClast when

given with etravirine versus administration alone were: caffeine/paraxanthine 0.91 (90% CI 0.85, 0.96), S-warfarin/7-OH-S-

warfarin 1.82 (90% CI 1.51, 2.19), omeprazole/5-OH-omepra-

zole 4.32 (90% CI 3.74, 5.00), dextromethorphan/dextrorphan1.12 (90% CI 0.90, 1.38) andmidazolam/1-OH-midazolam 0.63

(90% CI 0.57, 0.70). Consistent with the in vivo data obtained in

formal drug-drug interaction studies, no clinically relevant ef-

fects on CYP1A2 or CYP2D6were demonstrated. Etravirine at

steady state was a weak inducer of CYP3A and aweak inhibitor

of CYP2C9. Furthermore, an inhibitory effect of etravirine on

CYP2C19 was observed.

A number of drug-drug interaction studies assessed the ef-

fect of etravirine on other drugs and vice versa.[23-31] Two-way

drug-drug interaction studies at steady state were conducted

with the antiretrovirals didanosine, tenofovir disoproxil fu-

marate, indinavir, atazanavir, maraviroc (with or without

darunavir/ritonavir), raltegravir, elvitegravir/ritonavir and the

ritonavir-boosted protease inhibitors saquinavir, lopinavir,

atazanavir, darunavir and tipranavir. Two-way drug-drug

interaction studies at steady state were also conducted with

rifabutin, atorvastatin, paroxetine and clarithromycin. The

effect of full-dose ritonavir, efavirenz or nevirapine, and the

effect of omeprazole or ranitidine, all at steady state, on

single-dose etravirine were assessed as well as the effect of

etravirine at steady state on saquinavir, fosamprenavir/ritonavir,lopinavir/saquinavir/ritonavir, methadone, oral contraceptives



(ethinylestradiol/norethisterone), single-dose digoxin and

sildenafil.

Most of these trials used the commercial formulation of

etravirine. A specific drug-drug interaction trial with tenofovir

disoproxil fumarate that had been conducted with 800mg

etravirine twice daily administered as the experimental for-

mulation was repeated with 200mg etravirine twice daily ad-

ministered as the commercial formulation to assess potential

differences in the magnitude and direction of drug-drug inter-

actions between formulations. When comparing the two for-

mulations of etravirine administered alone as either 800mg

twice daily (4 · 200mg tablets) of the experimental formulation

to 200mg twice daily (2 · 200mg tablets) of the commercial

formulation, comparable mean exposures were observed.[18]

Coadministration of tenofovir disoproxil fumarate 300mg

once daily with etravirine 800mg twice daily (experimental

formulation) or 200mg twice daily (commercial formulation) in

two separate studies resulted in a consistent effect of either drug

on the other.

3.2.1 Effect of Etravirine on Coadministered Drugs

Etravirine had no clinically relevant effect on didanosine,

tenofovir disoproxil fumarate, raltegravir, elvitegravir/ritonaviror the boosted protease inhibitors darunavir, lopinavir, saqui-

navir, atazanavir or tipranavir (table III). Etravirine sig-

nificantly decreased unboosted indinavir and saquinavir

exposure and atazanavir trough concentrations, thus un-

boosted protease inhibitors are not recommended for coadmi-

nistration.

Coadministration of etravirine with atazanavir/ritonavirsignificantly decreased atazanavir Cmin (38%);[31] the clinical

relevance of this finding is unknown. Although guidelines re-

commend maintaining a trough concentration of atazanavir

above 150 ng/mL for wild-type HIV,[32] no recommendations

have been made in this document for resistant HIV. In several

trials where atazanavir concentrations were measured and re-

lated to efficacy, no relationship between the pharmacokinetics

of atazanavir and virological activity was established; con-

sistently amongst the trials, the number of protease mutations

was more predictive of atazanavir response.[33-37]

Etravirine increased exposure to amprenavir by 69% when

fosamprenavir/ritonavir was administered as 700mg/100mg

twice daily. The mechanism of this interaction is unknown.

Although high doses of fosamprenavir/ritonavir (i.e.

1400mg/100mg twice daily) with comparable exposures have

been investigated,[38,39] the safety of amprenavir at elevated

exposures is unknown; therefore, caution should be used

when coadministering etravirine and fosamprenavir/ritonavir.

A dose reduction of fosamprenavir may be needed; this can be

achieved with the oral solution.

Exposure tomaraviroc was decreased 53% by etravirine thus

the recommended dose of maraviroc is 600mg twice daily if

these drugs are coadministered without a boosted protease in-

hibitor or other potent CYP3A inhibitor in the regimen.[24]

However, this effect was counterbalanced in the presence of

boosted darunavir, requiring a dose reduction of maraviroc by

50% (150mg twice daily), consistent with previous reported

data for boosted protease inhibitors. When coadministering

maraviroc with etravirine and a boosted protease inhibitor,

the local prescribing information for maraviroc should be

consulted for the appropriate dose of maraviroc treating etra-

virine as a CYP3A inducer (e.g. efavirenz). No dose adjust-

ment for etravirine is necessary when coadministered with

maraviroc.

Etravirine decreased exposure to atorvastatin by 37% and to

clarithromycin 39%, while the active metabolites 2-OH-

atorvastatin and 15-OH-clarithromycin increased 1.27-fold

and 1.21-fold, respectively.[28,40] Since the net effect is a slight

decrease of the parent compound and a slight increase of the

active metabolite in both cases, no dose adjustments are sug-

gested for either atorvastatin or clarithromycin. As 14-OH-

clarithromycin has reduced activity against Mycobacterium

avium complex, overall activity against this pathogen may be

altered. Alternatives to clarithromycin should be considered for

the treatment ofM. avium complex. Exposure to both sildenafil

and its metabolite N-desmethyl sildenafil were decreased by

57% and 41%, respectively, when administered concomitantly

with etravirine at steady-state;[41] dose adjustment of sildenafil

may be therefore required.

No clinically relevant changes were demonstrated in the

pharmacokinetics of rifabutin, paroxetine, oral contraceptives,

digoxin or methadone when coadministered with etravirine

(table III).

3.2.2 Effect of Coadministered Drugs on Etravirine

The changes observed in etravirine pharmacokinetics when

combined with didanosine, tenofovir disoproxil fumarate,

darunavir/ritonavir, atazanavir (with or without low-dose

ritonavir), raltegravir, elvitegravir/ritonavir, maraviroc, rifa-

butin, clarithromycin, omeprazole or ranitidine are not con-

sidered clinically relevant (table IV).

Omeprazole, clarithromycin and (boosted) atazanavir in-

creased exposure to etravirine by 30–50%. In both ongoing

phase III trials in treatment-experienced patients, the safety and

tolerability profile of etravirine was generally comparable with

placebo, except for rash.[42,43] No relationship was observed



Table III. Effect of etravirine on pharmacokinetics of coadministered drug[23-31]

Coadministered drug Dose/schedule of

coadministered drug

No. of subjects Exposure Mean ratio of coadministered drug pharmacokinetic parameters

(90% CI; no effect = 1.00)

Cmax AUC Cmin

Coadministration with protease inhibitors

Indinavir 800 mg tid 10 k 0.72

(0.58, 0.89)

0.54

(0.46, 0.62)

0.24a

(0.18, 0.34)

Saquinavir 1200 mg single dose 12 k 0.54

(0.34, 0.86)

0.48

(0.29, 0.80)

NA

Atazanavir 400 mg od 14 k 0.97

(0.73, 1.29)

0.83

(0.63, 1.09)

0.53

(0.38, 0.73)

Atazanavir/ritonavir 300 mg/100 mg od 13 k 0.97

(0.89, 1.05)

0.86

(0.79, 0.93)

0.62

(0.55, 0.71)

Darunavir/ritonavir 600 mg/100 mg bid 15 2 1.11

(1.01, 1.22)

1.15

(1.05, 1.26)

1.02

(0.90, 1.17)

Fosamprenavir/ritonavir 700 mg/100 mg bid 8 m 1.62

(1.47, 1.79)

1.69

(1.53, 1.86)

1.77

(1.39, 2.25)

Lopinavir/ritonavir

(soft gel capsule)

400 mg/100 mg bid 14 k 0.85

(0.62, 1.05)

0.80

(0.49, 1.07)

0.92

(0.15, 1.68)

Saquinavir/ritonavir 1000 mg/100 mg bid 15 2 1.00

(0.70, 1.42)

0.95

(0.64, 1.42)

0.80

(0.46, 1.38)

Tipranavir/ritonavir 500 mg/200 mg bid 19 m 1.14

(1.02, 1.27)

1.18

(1.03, 1.36)

1.24

(0.96, 1.59)

Coadministration with nucleoside/nucleotide reverse transcriptase inhibitors

Didanosine 400 mg od 14 2 0.91

(0.58, 1.42)

0.99

(0.79, 1.25)

NA

Tenofovir disoproxil fumarate 300 mg od 19 2 1.15

(1.04, 1.27)

1.15

(1.09, 1.21)

1.19

(1.13, 1.26)

Coadministration with HIV-integrase inhibitors

Raltegravir 400 mg bid 19 k 0.89

(0.68, 1.15)

0.90

(0.68, 1.18)

0.66

(0.34, 1.26)

Elvitegravir/ritonavir 150 mg/100 mg od 17 2 1.07

(1.01, 1.13)

1.06

(1.00, 1.13)

1.06

(0.97, 1.16)

Coadministration with CCR5 antagonists

Maraviroc 300 mg bid 14 k 0.40

(0.28, 0.57)

0.47

(0.38, 0.58)

0.61

(0.53, 0.71)

Continued next page

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Table III. Contd


coadministered drug

No. of subjects Exposure Mean ratio of coadministered drug pharmacokinetic parameters

(90% CI; no effect = 1.00)

Cmax AUC Cmin

Coadministration with other drugs

Atorvastatin 40 mg od 16 k 1.04

(0.84, 1.30)

0.63

(0.58, 0.68)

NA

2-Hydroxy-atorvastatin 16 m 1.76

(1.60, 1.94)

1.27

(1.19, 1.36)

NA

Clarithromycin 500 mg bid 15 k 0.66

(0.57, 0.77)

0.61

(0.53, 0.69)

0.47

(0.38, 0.57)

14-Hydroxy-clarithromycin 15 m 1.33

(1.13, 1.56)

1.21

(1.05, 1.39)

1.05

(0.90, 1.22)

Digoxin 0.5 mg single dose 16 m 1.19

(0.96, 1.49)

1.18

(0.90, 1.56)

NA

Ethinylestradiol 0.035 mg od 16 m 1.33

(1.21, 1.46)

1.22

(1.13, 1.31)

1.09

(1.01, 1.18)

Norethisterone 1 mg od 16 2 1.05

(0.98, 1.12)

0.95

(0.90, 0.99)

0.78

(0.68, 0.90)

R(-)methadone Individual dose

regimen ranging

from 60 to 130 mg/day

16 2 1.02

(0.96, 1.09)

1.06

(0.99, 1.13)

1.10

(1.02, 1.19)

S(+)methadone 16 2 0.89

(0.83, 0.97)

0.89

(0.82, 0.96)

0.89

(0.81, 0.98)

Paroxetine 20 mg od 16 2 1.06

(0.95, 1.20)

1.03

(0.90, 1.18)

0.87

(0.75, 1.02)

Rifabutin 300 mg od 12 k 0.90

(0.78, 1.03)

0.83

(0.75, 0.94)

0.76

(0.66, 0.87)

25-O-desacetylrifabutin 300 mg od 12 k 0.85

(0.72, 1.00)

0.83

(0.74, 0.92)

0.78

(0.70, 0.87)

Sildenafil 50 mg single dose 15 k 0.55

(0.40, 0.75)

0.43

(0.36, 0.51)

NA

N-desmethyl-sildenafil 15 k 0.75

(0.59, 0.96)

0.59

(0.52, 0.68)

NA

a Trough concentration.

AUC = area under the plasma concentration-time curve; bid = twice daily; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; NA = not available; od = once

daily; tid = three times daily; m indicates increase; k indicates decrease; 2 indicates no change.

Clin

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irine

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Table IV. Effect of coadministered drug on pharmacokinetics of etravirine[23-31]


coadministered drug

No. of subjects Exposure Mean ratio of etravirine pharmacokinetic parameters

(90% CI; no effect = 1.00)

Cmax AUC Cmin

Coadministration with non-nucleoside reverse transcriptase inhibitors

Efavirenz 600 mg od 12 k 0.83

(0.73, 0.93)

0.59

(0.52, 0.68)

NA

Nevirapine 200 mg bid 5 k 0.64a 0.45a NA

Coadministration with protease inhibitors

Indinavir 800 mg tid 10 m 1.51

(1.16, 1.97)

1.51

(1.20, 1.90)

1.52b

(1.20, 1.91)

Atazanavir 400 mg od 14 m 1.47

(1.36, 1.59)

1.50

(1.41, 1.59)

1.58

(1.46, 1.70)

Atazanavir/ritonavir 300 mg/100 mg od 14 m 1.30

(1.17, 1.44)

1.30

(1.18, 1.44)

1.26

(1.12, 1.42)

Darunavir/ritonavir 600 mg/100 mg bid 14 k 0.68

(0.57, 0.82)

0.63

(0.54, 0.73)

0.51

(0.44, 0.61)

Lopinavir/ritonavir

(soft gel capsule)

400 mg/100 mg bid 13 m 1.15

(0.94, 1.41)

1.17

(0.96, 1.43)

1.23

(0.98, 1.53)

Ritonavir 600 mg bid 11 k 0.68

(0.55, 0.85)

0.54

(0.41, 0.73)

NA

Saquinavir/ritonavir 1000 mg/100 mg bid 14 k 0.63

(0.53, 0.75)

0.67

(0.56, 0.80)

0.71

(0.58, 0.87)

Tipranavir/ritonavir 500 mg/200 mg bid 19 k 0.29

(0.22, 0.40)

0.24

(0.18, 0.33)

0.18

(0.13, 0.25)

Coadministration with nucleoside/nucleotide reverse transcriptase inhibitors

Didanosine 400 mg od 15 2 1.16

(1.02, 1.32)

1.11

(0.99, 1.25)

1.05

(0.93, 1.18)

Tenofovir disoproxil fumarate 300 mg od 23 k 0.81

(0.75, 0.88)

0.81

(0.75, 0.88)

0.82

(0.73, 0.91)

Coadministration with HIV-integrase inhibitors

Raltegravir 400 mg bid 19 2 1.04

(0.97, 1.12)

1.10

(1.03, 1.16)

1.17

(1.10, 1.26)

Elvitegravir/ritonavir 150 mg/100 mg od 14 2 1.02

(0.86, 1.20)

0.98

(0.88, 1.08)

0.90

(0.83, 0.97)

Coadministratoin with CCR5 antagonists

Maraviroc 300 mg bid 14 2 1.05

(0.95, 1.17)

1.06

(0.99, 1.14)

1.08

(0.98, 1.19)

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between the incidence and severity of adverse events and

pharmacokinetic parameters of etravirine.[44,45] Considering

the lack of association between safety and pharmacokinetics of

etravirine, this increase of exposure to etravirine is deemed

clinically not relevant.

The decrease in exposure to etravirine by 37%when rifabutin

is coadministered is comparable to the effect of boosted pro-

tease inhibitors. Exposure to etravirine is also 37% lower when

combined with darunavir/ritonavir.[46] The efficacy of etravir-

ine was demonstrated in both DUET trials in the presence of

darunavir/ritonavir. In a phase IIb dose-ranging trial, demon-

strating an approximately 30% difference in exposure between

HIV-infected subjects using ritonavir-boosted protease in-

hibitors (lopinavir/ritonavir AUC 6074 – 6380 ng�h/mL) ver-

sus patients who did not have a protease inhibitor in their

antiretroviral regimen (AUC 7964 – 5850 ng�h/mL), no dif-

ference in antiviral efficacy was observed. When constructing a

regimenwith the addition of rifabutin, the antiviral efficacy and

interaction potential of other coadministered drugs such as

(boosted) protease inhibitors should be taken into account.

Etravirine exposure decreased with tipranavir/ritonavir(76%), efavirenz (41%), nevirapine (55%) and high-dose rito-

navir (46%) and, therefore, it is not recommended to coad-

minister etravirine with these medications.[25]

When coadministered with lopinavir/saquinavir/ritonavir,fosamprenavir/ritonavir, methadone, oral contraceptives, di-

goxin or sildenafil, the pharmacokinetics of etravirine were

comparable with historical controls.

In summary, etravirine can be combined with many drugs

without dose adjustment. Dose adjustments may be required

for (fos)amprenavir and sildenafil; the concomitant use of

atazanavir is recommended only in the presence of low-dose

ritonavir. Etravirine is not recommended in combination with

tipranavir/ritonavir. Use of an alternative to clarithromycin is

suggested when treating M. avium complex. Of note, the local

prescribing information for etravirine should always be con-

sulted when coadministering etravirine with other agents.

4. Pharmacodynamics

Both week 24 and 48 analyses of the separate DUET-1 and

DUET-2 trials demonstrated superior efficacy of etravirine com-

pared with placebo when added to an underlying antiretroviral

therapy including darunavir/ritonavir.[42,43,47-48] In the pooled

analysis of DUET-1 and -2 at week 48, a significantly higher

proportion of patients randomized to etravirine achieved

a confirmed viral load <50 HIV-1 RNA copies/mL (61%, time

to loss of virological response [TLOVR] definition) comparedTab

leIV

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Exposure

Mean

ratio

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para

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(90

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40

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od

16

20.9

7

(0.9

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2)

1.0

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(0.9

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7)

1.1

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(1.0

2,1.1

9)

Cla

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15

m1.4

6

(1.3

8,1.5

6)

1.4

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(1.3

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1.4

6

(1.3

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8)

Paro

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20

mg

od

16

21.0

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(0.9

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(0.9

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1.0

7

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Om

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40

mg

od

18

m1.1

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(0.9

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1.4

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NA

Ranitid

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150

mg

bid

18

k0.9

4

(0.7

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7)

0.8

6

(0.7

6,0.9

7)

NA

Rifabutin

300

mg

od

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k0.6

3

(0.5

3,0.7

4)

0.6

3

(0.5

4,0.7

4)

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5

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with placebo (40%).[49] Subgroup analyses indicated that the

use of etravirine substantially improved virological response

rates compared with placebo irrespective of race, age, sex,

region, baseline plasma viral load, baseline CD4 cell count,

hepatitis co-infection status, and HIV-1 clade (B vs non-B). An

added benefit of etravirine was observed regardless of previous

nevirapine or efavirenz experience. Treatment with etravirine

was also associated with a significantly greater mean change

from baseline (imputed) in log10 plasma viral load at week 48

(-2.25 HIV-1 RNA copies/mL) compared with placebo (-1.49HIV-1 RNA copies/mL). Increase of absolute and percentage

CD4 cell count was more pronounced in the etravirine group

than in the placebo group at all timepoints up to week 48. The

mean change from baseline in absolute CD4 cell count at week

48 was +98.2 and +72.8 · 106 cells/L in the etravirine and

placebo groups, respectively. The beneficial effect of etravirine

on the absolute and percentage CD4 cell count was observed at

all timepoints up to week 48.[50]

The effect of etravirine on achieving viral load <50 copies/mL

(TLOVR) at week 24 from various prognostic factors including

pharmacokinetic parameters (AUC12 and C0) was evaluated

using logistic regression with generalized additive modelling.

Baseline CD4 cell count, phenotypic fold-change in darunavir,

phenotypic fold change in etravirine, baseline viral load, phe-

notypic sensitivity score at baseline, adherence and use of en-

fuvirtide were all identified as prognostic factors in this analysis.

The pharmacokinetic exposure parameters of etravirine were

not retained as prognostic factors. At week 24, the predicted

probability of virological response (viral load <50 copies/mL)

increased with increasing baseline CD4 cell count, increasing

baseline phenotypic sensitivity score, and increasing adherence.

The predicted probability of response decreased with an in-

creasing phenotypic fold-change in darunavir or etravirine and

an increasing baseline viral load. Finally, the predicted prob-

ability of response was somewhat higher in subjects with de novo

use of enfuvirtide. Taken together, drug- disease- and subject-

related factors are important determinants of virological

response to etravirine. Pharmacokinetic parameters alone do

not appear to predict virological response at week 48. Similarly

to the phase IIb trials with etravirine, the pooled data of the

DUET trials failed to demonstrate any association between

adverse events and pharmacokinetics of etravirine.[45]

5. Conclusions

Etravirine is a valuable addition to the currently available

treatment options for HIV infection. The interaction potential

of etravirine is predictable and manageable, and necessitates

dose modifications of some of the coadministered drugs but not

for etravirine. The lack of pharmacokinetic-pharmacodynamic

relationships in terms of its efficacy and safety suggests a large

therapeutic window. Further pharmacokinetic research of

etravirine involves the evaluation of special populations, once-

daily regimens, drug-drug interactions and the development of

formulations with higher drug loads.

Acknowledgements

All authors are employees of Tibotec BVBA (Mechelen, Belgium) or

Tibotec Inc., (Yardley, PA, USA). Funding of research mentioned in this

manuscript has been provided by Tibotec Pharmaceuticals. The design

and conduct of trials and the collection, management, analysis and

interpretation of the data were performed under the supervision and final

responsibility of Tibotec Pharmaceuticals. In addition, Tibotec Pharma-

ceuticals was involved in the preparation, review and approval of this

manuscript. Drug interaction trials with tipranavir, elvitegravir, maraviroc

and raltegravir were conducted in cooperation with Boehringer Ingelheim

GmbH, Gilead Sciences, Inc., Pfizer Global Research and Development,

and Merck & Co., Inc., respectively.

Substantial contribution to the results presented in this manuscript has

been provided by all members of the TMC125 development teams.

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2008 Aug 2-8; Mexico City

Correspondence: Dr Monika Scholler-Gyure, Tibotec BVBA, Generaal De

Wittelaan L11B 3, B-2800 Mechelen, Belgium.

Email: [email protected]



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Clinical Pharmacokinetics and Pharmacodynamics of Etravirine