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REVIEW ARTICLE

Clin Pharmacokinet 2009; 48 (9): 561-574 0312-5963/09/0009-0561/$49.95/0

2009 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics and Pharmacodynamics of Etravirine


re,1 Thomas N. Kakuda,2 Araz Raoof,1 Goedele De Smedt1 and Richard M.W. Hoetelmans1 ller-Gyu Monika Scho
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, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate 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 3040 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated 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.

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Etravirine (formerly known as TMC125) is a novel diarylpyrimidine (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 mutations in the binding pocket are present. Significant in vitro activity 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 harbouring 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 pharmacodynamic properties of etravirine.

N N

NH

Br NH2

Fig. 1. Chemical structure 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 formulations with etravirine in an amorphous form homogenously dispersed in a polymer matrix. The currently marketed 100 mg 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

small intestine as the major site of absorption. In vitro studies conducted with 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 bioavailability of etravirine. The effect of meals 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 breakfast. In contrast, no significant difference has been observed in the pharmacokinetics of etravirine when given following a standardized breakfast (561 kCal, 15 g fat) versus a high-fat breakfast (1160 kCal, 70 g fat). Exposure to etravirine after intake following a croissant (345 kCal, 17 g fat) or an enhanced-fibre breakfast (685 kCal, 3 g 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 products 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 administer 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 study with a single dose of etravirine given with steady-state ranitidine or omeprazole treatment demonstrated no clinically relevant effect when etravirine was coadministered with these acid suppressing agents, suggesting that alterations in pH do not affect the bioavailability of etravirine.[8]
2.2 Distribution

Maximum plasma concentrations are generally reached within 45 hours after administration,[4,5] suggesting the proximal
2009 Adis Data Information BV. All rights reserved.

Etravirine is extensively bound (99.9%) to albumin and a1-acid glycoprotein, with a blood to plasma concentration ratio
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of 0.7.[9] The apparent volume of distribution of etravirine for the central compartment is 422 L.[5] The distribution of etravirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans, 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 3040 hours.
HO Br O N C N HN N NH2

Overall, etravirine metabolism is mainly catalysed by cytochrome 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
HO Br O NH2 N C N OH HN N

Oxidation urine, faeces and plasma

C N

C N

Metabolite 12
HO

Metabolite 8 N
O

Br NH2 N HN

Oxidation faeces and plasma

Metabolite 13
C N

Glucuronidation urine

Oxidation faeces
Br O N C N N NH2

Glucuronidation urine and plasma

Etravirine (TMC125) HN

C N

HO Br O N C HN N NH2

Metabolite 6

Glucuronidation N

HO Br O N C OH HN N NH2

Metabolite 1

Glucuronidation N

Fig. 2. Metabolism of etravirine.


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

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the in vitro results.[11] Most of the etravirine-related radioactivity was excreted in faeces as unchanged drug. No unchanged etravirine was detected in the urine. No pharmacological activity was demonstrated for the metabolites of etravirine in the presence of NNRTI-resistant HIV.[12]
2.4 Dose and Formulation Selection

Based on the relatively long elimination half-life, a oncedaily dosing regimen was a plausible option for etravirine administration. 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 development programme. In a dose-finding phase II trial, etravirine administered with an investigator-selected optimized background regimen consisting of at least two antiretrovirals (NRTI or NNRTI and/or lopinavir/ritonavir and/or enfuvirtide) was effective after 48 weeks at both doses of etravirine tested (400 mg and 800 mg twice daily of the experimental formulation) compared with a control group that received at least three investigator-selected antiretrovirals. Patients receiving 800 mg twice daily of etravirine showed a 1.01 log10 reduction in HIV RNA, versus a 0.14 log10 reduction in the control group after 48 weeks.[13] Treatment with etravirine was generally safe and well tolerated.[14] Based on the results of the phase IIb trials, the dose of 800 mg twice daily, i.e. four 200 mg tablets of the experimental formulation twice daily was selected. In parallel with the phase IIb trial, a spray-dried formulation of etravirine was developed to improve bioavailability and reduce pill burden. A comparative multiple dose bioavailability trial in HIV-infected patients demonstrated that the phase III

solid dispersion formulation at a dosage of 200 mg twice daily provides a pharmacokinetic profile comparable with 800 mg twice daily of the experimental formulation, with reduced interindividual variability. In summary, a dosage of etravirine 200 mg twice daily, i.e. two 100 mg 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 25 mg 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 etravirine 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 bioavailability trial in healthy HIV-negative adults demonstrated no relevant changes in oral bioavailability of etravirine when administered as four 25 mg tablets (whole) or as one 100 mg tablet dispersed in water, compared with one 100 mg tablet swallowed whole.[16] Etravirine dispersed in water is tasteless and odourless. Etravirine is stable in water at ambient temperatures 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 concentration (Cmin) of etravirine was 2526% lower with the once daily regimen compared with the twice daily regimen of the same daily dose; the maximum plasma concentration (Cmax) was approximately 4244% 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 No. of subjects tmax [h]b C0 [ng/mL] Cmax [ng/mL] AUC12 [ng h/mL] AUC24 [ng h/mL] 23 4.0 (2.06.0) 234 92 471 141 3925 1251 8054 2748 200 mg od 24 4.0 (2.06.0) 167 77 659 177 200 mg bid 39 4.08 (2.086.08) 530 173 959 278 8195 2428 17 220 5009 400 mg od 37 4.08 (3.086.13) 382 145 1393 386

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

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1800 Plasma concentration (ng/mL) 1600 1400 1200 1000 800 600 400 200 0 0 4 8 12 Time (h) 16

Etravirine 400 mg od Etravirine 200 mg bid

netic multiple-dose, two-period, crossover trials administering etravirine following a meal in once daily or twice daily regimens, 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

20

24

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).

daily (figure 3).[4] Etravirine is approved at a dosage of 200 mg 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 100400 mg.[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 parameters 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 200 mg twice daily when administered following a meal is approximately 30% (coefficient of variation [CV]).[4,17,18] Based on data of two pharmacoki-

A summary of the steady-state pharmacokinetics of etravirine in HIV-1 infected patients participating in pharmacokinetic 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 600 mg/100 mg twice daily, a drug known to interact with etravirine (see section 3). A two-compartmental model with sequential zero- and first-order absorption including 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 bioavailability was 40%. The effect of intrinsic and extrinsic factors (age, bodyweight, sex, race, hepatitis coinfection status, adherence as measured by pill count, use of enfuvirtide and use of tenofovir disoproxil fumarate) on the pharmacokinetics of etravirine was also assessed 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

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] mean SD C0 [ng/mL] Cmax [ng/mL] tmax [h] AUC12 [ng h/mL] 545 819 880 1030 median (range) 260 (1103960) 525 (2854980) 4 (06) Week 24 [n = 23] mean SD 446 533 797 668 median (range) 297 (752710) 586 (1993130) 4 (16) 7034 7238 5253 (170935 570)

7964 11 180

4307 (228453 870)

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.
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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 associated 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

shown to be considerably higher than expected plasma concentrations. 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 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, body mass 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 200 mg 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 potential 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 determined in human primary hepatocyte cultures, demonstrating an increase in CYP3A4 activity. The apparent etravirine concentration that produces 50% inhibition of P-glycoprotein was
2009 Adis Data Information BV. All rights reserved.

The in vivo interaction potential of a single dose and steadystate etravirine was evaluated in a two-period crossover study in 14 healthy HIV-negative subjects using the modified Cooperstown 5 + 1 cocktail (150 mg caffeine [CYP1A2], 10 mg warfarin + 10 mg vitamin K [CYP2C9], 40 mg omeprazole [CYP2C19], 30 mg dextromethorphan [CYP2D6] orally, and 0.025 mg/kg midazolam intravenously [CYP3A]).[21,22] After 14 days treatment with 200 mg etravirine twice daily the AUC from time zero to last measured concentration (AUClast) leastsquares mean (LSM) ratios for the cocktail compounds coadministered 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-Swarfarin 1.82 (90% CI 1.51, 2.19), omeprazole/5-OH-omeprazole 4.32 (90% CI 3.74, 5.00), dextromethorphan/dextrorphan 1.12 (90% CI 0.90, 1.38) and midazolam/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 effects on CYP1A2 or CYP2D6 were demonstrated. Etravirine at steady state was a weak inducer of CYP3A and a weak inhibitor of CYP2C9. Furthermore, an inhibitory effect of etravirine on CYP2C19 was observed. A number of drug-drug interaction studies assessed the effect 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 fumarate, 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
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(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 800 mg etravirine twice daily administered as the experimental formulation was repeated with 200 mg etravirine twice daily administered as the commercial formulation to assess potential differences in the magnitude and direction of drug-drug interactions between formulations. When comparing the two formulations of etravirine administered alone as either 800 mg twice daily (4 200 mg tablets) of the experimental formulation to 200 mg twice daily (2 200 mg tablets) of the commercial formulation, comparable mean exposures were observed.[18] Coadministration of tenofovir disoproxil fumarate 300 mg once daily with etravirine 800 mg twice daily (experimental formulation) or 200 mg 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/ritonavir or the boosted protease inhibitors darunavir, lopinavir, saquinavir, atazanavir or tipranavir (table III). Etravirine significantly decreased unboosted indinavir and saquinavir exposure and atazanavir trough concentrations, thus unboosted protease inhibitors are not recommended for coadministration. Coadministration of etravirine with atazanavir/ritonavir significantly decreased atazanavir Cmin (38%);[31] the clinical relevance of this finding is unknown. Although guidelines recommend 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 related to efficacy, no relationship between the pharmacokinetics of atazanavir and virological activity was established; consistently 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 700 mg/100 mg twice daily. The mechanism of this interaction is unknown. Although high doses of fosamprenavir/ritonavir (i.e. 1400 mg/100 mg 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.
2009 Adis Data Information BV. All rights reserved.

A dose reduction of fosamprenavir may be needed; this can be achieved with the oral solution. Exposure to maraviroc was decreased 53% by etravirine thus the recommended dose of maraviroc is 600 mg twice daily if these drugs are coadministered without a boosted protease inhibitor 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% (150 mg 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 etravirine as a CYP3A inducer (e.g. efavirenz). No dose adjustment for etravirine is necessary when coadministered with maraviroc. Etravirine decreased exposure to atorvastatin by 37% and to clarithromycin 39%, while the active metabolites 2-OHatorvastatin 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 suggested for either atorvastatin or clarithromycin. As 14-OHclarithromycin has reduced activity against Mycobacterium avium complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin should be considered for the treatment of M. 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, rifabutin, clarithromycin, omeprazole or ranitidine are not considered clinically relevant (table IV). Omeprazole, clarithromycin and (boosted) atazanavir increased exposure to etravirine by 3050%. 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
Clin Pharmacokinet 2009; 48 (9)

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 Coadministration with protease inhibitors Indinavir 800 mg tid 10 k k k k 2 m k 2 m 0.72 (0.58, 0.89) 0.54 (0.34, 0.86) 0.97 (0.73, 1.29) 0.97 (0.89, 1.05) 1.11 (1.01, 1.22) 1.62 (1.47, 1.79) 0.85 (0.62, 1.05) 1.00 (0.70, 1.42) 1.14 (1.02, 1.27) 0.54 (0.46, 0.62) 0.48 (0.29, 0.80) 0.83 (0.63, 1.09) 0.86 (0.79, 0.93) 1.15 (1.05, 1.26) 1.69 (1.53, 1.86) 0.80 (0.49, 1.07) 0.95 (0.64, 1.42) 1.18 (1.03, 1.36) 0.24a (0.18, 0.34) NA AUC Cmin

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568

Saquinavir

1200 mg single dose

12

Atazanavir

400 mg od

14

0.53 (0.38, 0.73) 0.62 (0.55, 0.71) 1.02 (0.90, 1.17) 1.77 (1.39, 2.25) 0.92 (0.15, 1.68) 0.80 (0.46, 1.38) 1.24 (0.96, 1.59)

Atazanavir/ritonavir

300 mg/100 mg od

13

Darunavir/ritonavir

600 mg/100 mg bid

15

Fosamprenavir/ritonavir

700 mg/100 mg bid

Lopinavir/ritonavir (soft gel capsule) Saquinavir/ritonavir

400 mg/100 mg bid

14

1000 mg/100 mg bid

15

Tipranavir/ritonavir

500 mg/200 mg bid

19

Coadministration with nucleoside/nucleotide reverse transcriptase inhibitors Didanosine 400 mg od 14 2 2 0.91 (0.58, 1.42) 1.15 (1.04, 1.27) 0.99 (0.79, 1.25) 1.15 (1.09, 1.21) NA

Tenofovir disoproxil fumarate

300 mg od

19

1.19 (1.13, 1.26)

Coadministration with HIV-integrase inhibitors Raltegravir 400 mg bid 19 k 2 0.89 (0.68, 1.15) 1.07 (1.01, 1.13) 0.90 (0.68, 1.18) 1.06 (1.00, 1.13) 0.66 (0.34, 1.26) 1.06 (0.97, 1.16) re et al. ller-Gyu Scho

Elvitegravir/ritonavir

150 mg/100 mg od

17

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

Table III. Contd 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 Coadministration with other drugs Atorvastatin 40 mg od 16 k m k m m m 2 2 1.04 (0.84, 1.30) 1.76 (1.60, 1.94) 0.66 (0.57, 0.77) 1.33 (1.13, 1.56) 1.19 (0.96, 1.49) 1.33 (1.21, 1.46) 1.05 (0.98, 1.12) 1.02 (0.96, 1.09) 0.63 (0.58, 0.68) 1.27 (1.19, 1.36) 0.61 (0.53, 0.69) 1.21 (1.05, 1.39) 1.18 (0.90, 1.56) 1.22 (1.13, 1.31) 0.95 (0.90, 0.99) 1.06 (0.99, 1.13) NA AUC Cmin

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Clinical Pharmacology of Etravirine

2-Hydroxy-atorvastatin

16

NA

Clarithromycin

500 mg bid

15

0.47 (0.38, 0.57) 1.05 (0.90, 1.22) NA

14-Hydroxy-clarithromycin

15

Digoxin

0.5 mg single dose

16

Ethinylestradiol

0.035 mg od

16

1.09 (1.01, 1.18) 0.78 (0.68, 0.90) 1.10 (1.02, 1.19)

Norethisterone

1 mg od

16

R(-)methadone

Individual dose regimen ranging from 60 to 130 mg/day

16

S(+)methadone

16

2 2 k k k k

0.89 (0.83, 0.97) 1.06 (0.95, 1.20) 0.90 (0.78, 1.03) 0.85 (0.72, 1.00) 0.55 (0.40, 0.75) 0.75 (0.59, 0.96)

0.89 (0.82, 0.96) 1.03 (0.90, 1.18) 0.83 (0.75, 0.94) 0.83 (0.74, 0.92) 0.43 (0.36, 0.51) 0.59 (0.52, 0.68)

0.89 (0.81, 0.98) 0.87 (0.75, 1.02) 0.76 (0.66, 0.87) 0.78 (0.70, 0.87) NA

Paroxetine

20 mg od

16

Rifabutin

300 mg od

12

25-O-desacetylrifabutin

300 mg od

12

Sildenafil

50 mg single dose

15

N-desmethyl-sildenafil a Trough concentration.

15

NA

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. 569

Table IV. Effect of coadministered drug on pharmacokinetics of etravirine[23-31] Coadministered drug Dose/schedule of coadministered drug No. of subjects Exposure Mean ratio of etravirine pharmacokinetic parameters (90% CI; no effect = 1.00) Cmax Coadministration with non-nucleoside reverse transcriptase inhibitors Efavirenz Nevirapine 600 mg od 200 mg bid 12 5 k k 0.83 (0.73, 0.93) 0.64a 0.59 (0.52, 0.68) 0.45a NA NA AUC Cmin

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570

Coadministration with protease inhibitors Indinavir Atazanavir Atazanavir/ritonavir Darunavir/ritonavir Lopinavir/ritonavir (soft gel capsule) Ritonavir Saquinavir/ritonavir Tipranavir/ritonavir 800 mg tid 400 mg od 300 mg/100 mg od 600 mg/100 mg bid 400 mg/100 mg bid 600 mg bid 1000 mg/100 mg bid 500 mg/200 mg bid 10 14 14 14 13 11 14 19 m m m k m k k k 1.51 (1.16, 1.97) 1.47 (1.36, 1.59) 1.30 (1.17, 1.44) 0.68 (0.57, 0.82) 1.15 (0.94, 1.41) 0.68 (0.55, 0.85) 0.63 (0.53, 0.75) 0.29 (0.22, 0.40) 1.51 (1.20, 1.90) 1.50 (1.41, 1.59) 1.30 (1.18, 1.44) 0.63 (0.54, 0.73) 1.17 (0.96, 1.43) 0.54 (0.41, 0.73) 0.67 (0.56, 0.80) 0.24 (0.18, 0.33) 1.52b (1.20, 1.91) 1.58 (1.46, 1.70) 1.26 (1.12, 1.42) 0.51 (0.44, 0.61) 1.23 (0.98, 1.53) NA 0.71 (0.58, 0.87) 0.18 (0.13, 0.25)

Coadministration with nucleoside/nucleotide reverse transcriptase inhibitors Didanosine Tenofovir disoproxil fumarate 400 mg od 300 mg od 15 23 2 k 1.16 (1.02, 1.32) 0.81 (0.75, 0.88) 1.11 (0.99, 1.25) 0.81 (0.75, 0.88) 1.05 (0.93, 1.18) 0.82 (0.73, 0.91)

Coadministration with HIV-integrase inhibitors Raltegravir Elvitegravir/ritonavir 400 mg bid 150 mg/100 mg od 19 14 2 2 1.04 (0.97, 1.12) 1.02 (0.86, 1.20) 1.10 (1.03, 1.16) 0.98 (0.88, 1.08) 1.17 (1.10, 1.26) 0.90 (0.83, 0.97) re et al. ller-Gyu Scho

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)
Continued next page

Clinical Pharmacology of Etravirine

571

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.

Dose/schedule of coadministered drug

500 mg bid

150 mg bid

40 mg od

20 mg od

40 mg od

300 mg od

a CIs not available due to limited sample size.

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 protease inhibitors. Exposure to etravirine is also 37% lower when combined with darunavir/ritonavir.[46] The efficacy of etravirine was demonstrated in both DUET trials in the presence of darunavir/ritonavir. In a phase IIb dose-ranging trial, demonstrating an approximately 30% difference in exposure between HIV-infected subjects using ritonavir-boosted protease inhibitors (lopinavir/ritonavir AUC 6074 6380 ng h/mL) versus patients who did not have a protease inhibitor in their antiretroviral regimen (AUC 7964 5850 ng h/mL), no difference in antiviral efficacy was observed. When constructing a regimen with 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 ritonavir (46%) and, therefore, it is not recommended to coadminister etravirine with these medications.[25] When coadministered with lopinavir/saquinavir/ritonavir, fosamprenavir/ritonavir, methadone, oral contraceptives, digoxin 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 consulted when coadministering etravirine with other agents.

1.10 (1.02, 1.19)

1.46 (1.36, 1.58)

1.07 (0.98, 1.17)

Cmin

Mean ratio of etravirine pharmacokinetic parameters (90% CI; no effect = 1.00)

1.02 (0.97, 1.07)

1.42 (1.34, 1.50)

1.01 (0.93, 1.10)

1.41 (1.22, 1.62)

0.86 (0.76, 0.97)

AUC

0.63 (0.54, 0.74)

0.65 (0.56, 0.74)

NA

NA

0.97 (0.93, 1.02)

1.46 (1.38, 1.56)

1.05 (0.96, 1.15)

1.17 (0.96, 1.43)

0.94 (0.75, 1.17)

Exposure

Cmax

No. of subjects

16

16

18

15

Coadministration with other drugs

18

12

0.63 (0.53, 0.74)

4. Pharmacodynamics Both week 24 and 48 analyses of the separate DUET-1 and DUET-2 trials demonstrated superior efficacy of etravirine compared 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) compared
Clin Pharmacokinet 2009; 48 (9)

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b Trough concentration.

Coadministered drug

Table IV. Contd

Clarithromycin

Omeprazole

Atorvastatin

Paroxetine

Ranitidine

Rifabutin

572

re et al. ller-Gyu Scho

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 (-1.49 HIV-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, phenotypic sensitivity score at baseline, adherence and use of enfuvirtide 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 increasing phenotypic fold-change in darunavir or etravirine and an increasing baseline viral load. Finally, the predicted probability of response was somewhat higher in subjects with de novo use of enfuvirtide. Taken together, drug- disease- and subjectrelated 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
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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, oncedaily 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 Pharmaceuticals 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.

References
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no. PL5.2]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12-16; Glasgow 26. Ramanathan S, West S, Kakuda TN, et al. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antiviral Ther 2008; 13 (8): 1011-7 27. Scho ller-Gyu re M, Kakuda TN, Bollen S, et al. No pharmacokinetic interaction between TMC125 (etravirine; TMC125) and paroxetine in HIV-negative volunteers [abstract no. P4.3/01]. 11th European AIDS Conference; 2007 Oct 24-27; Madrid 28. Scho ller-Gyu re M, Kakuda TN, De Smedt G, et al. Pharmacokinetic interaction between the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and atorvastatin in HIV-negative volunteers [abstract no. WEPEA106]. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2007 Jul 22-25; Sydney 29. Scho ller-Gyu re M, Kakuda TN, Van Solingen R, et al. No clinically relevant effect of etravirine (ETR; TMC125) on digoxin pharmacokinetics in HIVnegative volunteers [abstract no. P22]. 9th International Workshop on Clinical Pharmacology of HIV Therapy; 2008 Apr 7-9; New Orleans (LA) 30. Baede P, Piscitelli S, Graham N, et al. Drug interactions with TMC125, a potent next generation non-nocleoside reverse transcriptase inhibitor [abstract no. A-1827]. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, 2002 Sep 27-30; San Diego (CA) 31. Scho ller-Gyu re M, Woodfall B, De Marez T, et al. Pharmacokinetics of TMC125 with atazanavir and atazanavir/ritonavir [abstract no. P278]. 8th International Congress on Drug Therapy in HIV Infection; 2006 Nov 12-16; Glasgow 32. US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents [online]. Available from URL: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf [Accessed 2008 Sep 9] 33. Ray JE, Marriott D, Bloch MT, et al. Therapeutic drug monitoring of atazanavir: surveillance of pharmacotherapy in the clinic. Br J Clin Pharmacol 2005 Sep; 60 (3): 291-9 34. Cleijsen RM, van de Ende ME, Kroon FP, et al. Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice. J Antimicrob Chemother 2007 Oct; 60 (4): 897-900 35. Gianotti N, Soria A, Lazzarin A. Antiviral activity and clinical efficacy of atazanavir in HIV-1-infected patients: a review. New Microbiol 2007 Apr; 30 (2): 79-88 36. Pellegrin I, Breilh D, Ragnaud JM, et al. Virological responses to atazanavirritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study). Antivir Ther 2006; 11 (4): 421-9 37. Solas C, Colson P, Ravaux I, et al. The genotypic inhibitory quotient: a predictive factor of atazanavir response in HIV-1-infected treatment-experienced patients. J Acquir Immune Defic Syndr 2008 Jun 1; 48 (2): 177-80 38. Molina JM, Ait-Khaled M, Rinaldi R, et al. Fosamprenavir/ritonavir in advanced HIV disease (TRIAD): a randomized study of high-dose, dualboosted or standard dose fosamprenavir/ritonavir in HIV-1-infected patients with antiretroviral resistance. J Antimicrob Chemother 2009 Aug; 64 (2): 398-410 39. Shelton MJ, Wire MB, Lou Y, et al. Pharmacokinetic and safety evaluation of high-dose combinations of fosamprenavir and ritonavir. Antimicrob Agents Chemother 2006 Mar; 50 (3): 928-34 40. Scho ller-Gyu re M, Debroye C, Woodfall B, et al. Pharmacokinetic interaction between TMC125 and clarithromycin [abstract no. P1351]. 44th Annual Meeting, Infectious Diseases Society of America; 2006 Oct 12-15; Toronto 41. Scho ller-Gyu re M, Debroye C, Vyncke V, et al. Effect of TMC125 on sildenafil pharmacokinetics. 7th International Workshop of Clinical Pharmacology of HIV Therapy; 2006 Apr 20-22; Lisbon
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42. Madruga JV, Cahn P, Grinsztejn B, et al. 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 Jul 7; 370 (9581): 29-38 43. Lazzarin A, Campbell T, Clotet B, et al. 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 Jul 7; 370 (9581): 39-48 44. Kakuda TN, Scho ller-Gyu re M, Peeters M, et al. Pharmacokinetics and pharmacodynamics of TMC125 in HIV-infected patients with non-nucleoside reverse transcriptase inhibitor and protease inhibitor resistance: TMC125C223 [abstract no. L-131]. 14th Conference on Retroviruses and Opportunistic Infections; 2007 Feb 25-28; Los Angeles (CA) 45. Kakuda TN, Peeters M, Corbett C, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of etravirine (ETR) in treatment-experienced HIV-1 infected patients: pooled 48-week results of DUET-1 and DUET-2 [abstract no. H-4056]. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2008 Oct 25-28; Washington, DC 46. Scho ller-Gyu re M, Kakuda TN, Sekar V, et al. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther 2007; 12 (5): 789-96 47. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: Week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of etra-

virine (ETR; TMC125) versus placebo in 612 treatment-experienced HIV-1infected patients [abstract no. 790]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3-6; Boston (MA) 48. Johnson M, Campbell T, Clotet B, et al. DUET-2: Week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of etravirine (ETR; TMC125) versus placebo in 591 treatment-experienced HIV-1infected patients [abstract no. 791]. 15th Conference on Retroviruses and Opportunistic Infections; 2008 Feb 3-6; Boston (MA) 49. Trottier B, Johnson M, Katlama C, et al. Pooled 48-week analysis of DUET-I and DUET-2: durable efficacy and safety results of etravirine (ETR; TMC125) in treatment-experienced HIV-infected patients [abstract no. P167]. 17th Annual Canadian Conference on HIV/AIDS Research; 2008 Apr 24-27; Montreal 50. Cahn P, Molina JM, Towner W, et al. 48-week pooled analysis of DUET-1 and DUET-2: the impact of baseline characteristics on virological response to etravirine (TMC125; ETR) [abstract]. XIIth International AIDS Conference; 2008 Aug 2-8; Mexico City

re, Tibotec BVBA, Generaal De ller-Gyu Correspondence: Dr Monika Scho Wittelaan L11B 3, B-2800 Mechelen, Belgium. Email: mscholle@its.jnj.com

2009 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2009; 48 (9)