Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors
ATC code: J05AG04
Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme’s catalytic site.
Etravirine exhibits activity against wild type HIV-1 in T-cell lines and primary cells with median EC50 values ranging from 0.9 to 5.5 nM. Etravirine demonstrates activity against HIV-1 group M (subtypes A, B, C, D, E, F, and G) and HIV-1 group O primary isolates with EC50 values ranging from 0.3 to 1.7 nM and from 11.5 to 21.7 nM, respectively. Although etravirine demonstrates in vitro activity against wild type HIV-2 with median EC50 values ranging from 5.7 to 7.2 μM, treatment of HIV-2 infection with etravirine is not recommended in the absence of clinical data. Etravirine retains activity against HIV-1 viral strains resistant to nucleoside reverse transcriptase and/or protease inhibitors. In addition, etravirine demonstrates a fold change (FC) in EC50 ≤3 against 60% of 6,171 NNRTI-resistant clinical isolates.
Etravirine efficacy in relation to NNRTI resistance at baseline has mainly been analysed with etravirine given in combination with darunavir/ritonavir (DUET-1 and DUET-2). Boosted protease inhibitors, like darunavir/ritonavir, show a higher barrier to resistance compared to other classes of antiretrovirals. The breakpoints for reduced efficacy with etravirine (>2 etravirine-associated mutations at baseline, see clinical results section) applies when etravirine is given in combination with a boosted protease inhibitor. This breakpoint might be lower in antiretroviral combination therapy not including a boosted protease inhibitor.
In the Phase III trials DUET-1 and DUET-2, mutations that developed most commonly in patients with virologic failure to the etravirine containing regimen were V108I, V179F, V179I, Y181C and Y181I, which usually emerged in a background of multiple other NNRTI resistance-associated mutations (RAMs). In all the other trials conducted with etravirine in HIV-1 infected patients, the following mutations emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y.
Following virologic failure of an etravirine-containing regimen it is not recommended to treat patients with efavirenz and/or nevirapine.
The evidence of efficacy of etravirine is based on 48-week data from 2 Phase III trials DUET-1 and DUET-2. These trials were identical in design and similar efficacy for etravirine was seen in each trial. The results below are pooled data from the two trials.
Trial characteristics
Table 3. DUET-1 and DUET-2 pooled 48-week data:
| Etravirine + BR N=599 | Placebo + BR N=604 | Treatment difference (CI: 95%) | |
|---|---|---|---|
| Baseline characteristics | |||
| Median plasma HIV-1 RNA | 4,8 log10 copies/ml | 4,8 log10 copies/ml | |
| Median CD4 cell count | 99 × 106 cells/l | 109 × 106 cells/l | |
| Outcomes | |||
| Confirmed undetectable viral load (<50 HIV-1 RNA copies/ml)a n (%) | |||
| Overall | 363 (60,6%) | 240 (39,7%) | 20,9% (15,3%, 26,4%)d |
| de novo ENF | 109 (71,2%) | 93 (58,5%) | 12,8% (2,3%, 23,2%)f |
| Not de novo ENF | 254 (57,0%) | 147 (33,0%) | 23,9% (17,6%, 30,3%)f |
| <400 HIV-1 RNA copies//mla n (%) | 428 (71,5%) | 286 (47,4%) | 24,1% (18,7%, 29,5%)d |
| HIV-1 RNA log10 mean change from baseline (log10 copies/ml)b | -2,25 | -1,49 | -0,6 (-0,8, -0,5)c |
| CD4 cell count mean change from baseline (x 106/l)b | +98,2 | +72,9 | 24,4 (10,4, 38,5)c |
| Any AIDS defining illness and/or death n (%) | 35 (5,8%) | 59 (9,8%) | -3,9% (-6,9%, -0,9%)e |
a Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response).
b Non-completer is failure (NC = F) imputation.
c Treatment differences are based on Least Square Means from an ANCOVA model including the stratification factors. P-value<0.0001 for mean decrease in HIV-1 RNA; P-value=0.0006 for mean change in CD4 cell count.
d Confidence interval around observed difference of response rates; P-value<0.0001 from logistic regression model, including stratification factors.
e Confidence interval around observed difference of response rates; P-value=0.0408.
f Confidence interval around observed difference of response rates; P-value from CMH test controlling for stratification factors = 0.0199 for de novo, and <0.0001 for not de novo.
Since there was a significant interaction effect between treatment and ENF, the primary analysis was done for 2 ENF strata (patients reusing or not using ENF versus patients using ENF de novo). The week 48 results from the pooled analysis of DUET-1 and DUET-2 demonstrated that the etravirine arm was superior to the placebo arm irrespective of whether ENF was used de novo (p=0.0199) or not (p<0.0001). Results of this analysis (week 48 data) by ENF stratum are shown in table 3.
Significantly fewer patients in the etravirine arm reached a clinical endpoint (AIDS-defining illness and/or death) as compared to the placebo arm (p=0.0408).
A subgroup analysis of the virologic response (defined as a viral load <50 HIV-1 RNA copies/ml) at week 48 by baseline viral load and baseline CD4 count (pooled DUET data) is presented in table 4.
Table 4. DUET-1 and DUET-2 pooled data:
| Subgroups | Proportion of subjects with HIV-1 RNA <50 copies/ml at week 48 | |
|---|---|---|
| Etravirine + BR N=599 | Placebo + BR N=604 | |
| Baseline HIV-1 RNA | ||
| <30.000 copies/ml | 75,8% | 55,7% |
| ≥30.000 and <100.000 copies/ml | 61,2% | 38,5% |
| ≥100.000 copies/ml | 49,1% | 28,1% |
| Baseline CD4 count (x 106/l) | ||
| <50 | 45,1% | 21,5% |
| ≥50 and <200 | 65,4% | 47,6% |
| ≥200 and <350 | 73,9% | 52,0% |
| ≥350 | 72,4% | 50,8% |
Note: Imputations according to the TLOVR algorithm (TLOVR = Time to Loss of Virologic Response)
In DUET-1 and DUET-2, the presence at baseline of 3 or more of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S, (etravirine RAMs) was associated with a decreased virologic response to etravirine (see table 5). These individual mutations occurred in the presence of other NNRTI RAMs. V179F was never present without Y181C.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.
Table 5. Proportion of subjects with <50 HIV-1 RNA copies/ml at week 48 by baseline number of etravirine RAMs in the non-viral failure excluded population of pooled DUET-1 and DUET-2 trials:
| Baseline number of Etravirine RAMs* | Etravirine arms N=549 | |
|---|---|---|
| Reused/not used ENF | de novo ENF | |
| All ranges | 63,3% (254/401) | 78,4% (109/139) |
| 0 | 74,1% (117/158) | 91,3% (42/46) |
| 1 | 61,3% (73/119) | 80,4% (41/51) |
| 2 | 64,1% (41/64) | 66,7% (18/27) |
| ≥3 | 38,3% (23/60) | 53,3% (8/15) |
| Placebo arms N=569 | ||
| All ranges | 37,1% (147/396) | 64,1% (93/145) |
* Etravirine RAMs = V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S
Note: all patients in the DUET trials received a background regimen consisting of darunavir/rtv, investigator-selected NRTIs and optional enfuvirtide.
The presence of K103N alone, which was the most prevalent NNRTI mutation in DUET-1 and DUET-2 at baseline, was not identified as a mutation associated with resistance to etravirine. Furthermore, the presence of this mutation alone did not affect the response in the etravirine arm. Additional data is required to conclude on the influence of K103N when associated with other NNRTIs mutations.
Data from the DUET studies suggest that baseline fold change (FC) in EC50 to etravirine was a predictive factor of virologic outcome, with gradually decreasing responses observed above FC 3 and FC 13. FC subgroups are based on the select patient populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for etravirine.
TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigated the efficacy and safety of etravirine in a treatment regimen, which is not approved under the current indication. In the TMC125-C227 study, etravirine (N=59) was administered with 2 investigator-selected NRTIs (i.e. without a ritonavir-boosted PI) and compared to an investigator-selected combination of a PI with 2 NRTIs (N=57). The trial population included PI-naïve, NNRTI-experienced patients with evidence of NNRTI resistance.
At week 12, virologic response was greater in the control-PI arm (-2.2 log10 copies/ml from baseline; N=53) compared to the etravirine arm (-1.4 log10 copies/ml from baseline; N=40). This difference between treatment arms was statistically significant.
Based on these trial results, etravirine is not recommended for use in combination with N(t)RTIs only in patients who have experienced virological failure on an NNRTI- and N(t)RTI-containing regimen.
PIANO is a single-arm, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of etravirine in 101 antiretroviral treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age and weighing at least 16 kg. The study enrolled patients on a stable but virologically failing antiretroviral treatment regimen, with a confirmed HIV-1 RNA plasma viral load ≥500 copies/ml. Sensitivity of the virus to etravirine at screening was required.
The median baseline plasma HIV-1 RNA was 3.9 log10 copies/ml, and the median baseline CD4 cell count was 385 × 106 cells/l.
Table 6. Virologic responses (ITT – TLOVR), change from baseline in log10 viral load (NC = F), and change from baseline in CD4 percentage and cell count (NC = F) at week 24 in the TMC125-C213 and pooled DUET studies:
| Study | TMC125-C213 | TMC125-C213 | TMC125-C213 | Pooled DUET Studies |
|---|---|---|---|---|
| Age at screening | 6 to <12 years | 12 to <18 years | 6 to <18 years | ≥18 years |
| Treatment group | ETR N=41 | ETR N=60 | ETR N=101 | ETR N=599 |
| Virologic parameters | ||||
| Viral load <50 copies/ml at week 24, n (%) | 24 (58,5) | 28 (46,7) | 52 (51,5) | 363 (60,6) |
| Viral load <400 copies/ml at week 24, n (%) | 28 (68,3) | 38 (63,3) | 66 (65,3) | 445 (74,3) |
| ≥1 log10 decrease from baseline at week 24, n (%) | 26 (63,4) | 38 (63,3) | 64 (63,4) | 475 (79,3) |
| Change from baseline in log10 viral load (copies/ml) at week 24, mean (SE) and median (range) | -1,62 (0,21) -1,68 (-4,3, 0,9) | -1,44 (0,17) -1,68 (-4,0, 0,7) | -1,51 (0,13) -1,68 (-4,3, 0,9) | -2,37 (0,05) -2,78 (-4,6, 1,4) |
| Immunologic parameters | ||||
| Change from baseline in CD4 cell count (x 106 cells/l), mean (SE) and median (range) | 125 (33,0) 124 (-410, 718) | 104 (17,5) 81 (-243, 472) | 112 (16,9) 108 (-410, 718) | 83,5 (3,64) 77,5 (-331, 517) |
| Change from baseline in CD4 percentage, median (range) | 4% (-9, 20) | 3% (-4, 14) | 4% (-9, 20) | 3% (-7, 23) |
N = number of subjects with data; n = number of observations.
At week 48, 53.5% of all paediatric patients had a confirmed undetectable viral load <50 HIV-1 RNA copies/ml according to the TLOVR algorithm. The proportion of paediatric patients with <400 HIV-1 RNA copies/ml was 63.4%. The mean change in plasma HIV-1 RNA from baseline to week 48 was -1.53 log10 copies/ml, and the mean CD4 cell count increase from baseline was 156 × 106 cells/l.
The European Medicines Agency has deferred the obligation to submit the results of studies with INTELENCE in one or more subsets of the paediatric population in human immunodeficiency virus infection, as per Paediatric Investigation Plan (PIP) decision in the granted indication (see section 4.2 for information on paediatric use).
Etravirine (200 mg twice daily), evaluated in combination with other antiretroviral medicinal products in a study of 15 pregnant women during the second and third trimesters of pregnancy and postpartum, demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum, and less so for unbound etravirine exposure (see section 5.2). There were no new clinically relevant safety findings in the mothers or in the newborns in this trial.
The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult and paediatric treatment-experienced HIV-1 infected patients. Exposure to etravirine was lower (35-50%) in HIV-1 infected patients than in healthy subjects.
Table 7. Population pharmacokinetic estimates of etravirine 200 mg twice daily in HIV-1 infected adult subjects (integrated data from Phase III trials at week 48)*:
| Parameter | Etravirine 200 mg twice daily N=575 |
|---|---|
| AUC12h (ng.h/ml) | |
| Geometric Mean ± Standard Deviation | 4,522 ± 4,710 |
| Median (Range) | 4,380 (458 – 59,084) |
| C0h (ng/ml ) | |
| Geometric Mean ± Standard Deviation | 297±391 |
| Median (Range) | 298 (2 – 4,852) |
* All HIV-1 infected subjects enrolled in Phase III clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in the table account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of etravirine with darunavir/ritonavir.
Note: The median protein binding adjusted EC 50 for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/ml.
An intravenous formulation of etravirine is unavailable, thus, the absolute bioavailability of etravirine is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hours. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, medicinal products that are known to increase gastric pH.
The systemic exposure (AUC) to etravirine was decreased by about 50% when etravirine was administered under fasting conditions, as compared to administration following a meal. Therefore, INTELENCE should be taken following a meal.
Etravirine is approximately 99.9% bound to plasma proteins, primarily to albumin (99.6%) and α1-acid glycoprotein (97.66%-99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative metabolism by the hepatic cytochrome CYP450 (CYP3A) system and, to a lesser extent, by the CYP2C family, followed by glucuronidation.
After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of 14C-etravirine could be retrieved in faeces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in faeces. Unchanged etravirine in faeces is likely to be unabsorbed drug. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hours.
The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1 infected paediatric patients, 6 years to less than 18 years of age and weighing at least 16 kg, showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine 200 mg twice daily (see sections 4.2 and 5.2) when administered at a dose corresponding to 5.2 mg/kg twice daily. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarised in the table below.
Table 8. Population pharmacokinetic estimates for etravirine (all doses combined) in treatment-experienced HIV-1 infected paediatric patients 6 years to less than 18 years of age (PIANO 48 week analysis):
| Parameter | Etravirine N=101 |
|---|---|
| AUC12h (ng.h/ml) | |
| Geometric Mean ± Standard Deviation | 3,729 ± 4,305 |
| Median (Range) | 4,560 (62 – 28,865) |
| C0h (ng/ml) | |
| Geometric Mean ± Standard Deviation | 205 ± 342 |
| Median (Range) | 287 (2 – 2,276) |
The pharmacokinetics of etravirine in paediatric patients less than 6 years of age are under investigation. There are insufficient data at this time to recommend a dose in paediatric patients less than 6 years of age or weighing less than 16 kg (see section 4.2).
Population pharmacokinetic analysis in HIV infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18 to 77 years) evaluated, with 6 subjects aged 65 years or older (see sections 4.2 and 4.4).
No significant pharmacokinetic differences have been observed between males and females. A limited number of females were included in the studies.
Population pharmacokinetic analysis of etravirine in HIV infected patients indicated no apparent difference in the exposure to etravirine between Caucasian, Hispanic and Black subjects. The pharmacokinetics in other races have not been sufficiently evaluated.
Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh Class A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh Class B) hepatic impairment to 8 matched controls, the multiple dose pharmacokinetic disposition of etravirine was not altered in patients with mild to moderate hepatic impairment. However, unbound concentrations have not been assessed. Increased unbound exposure could be expected. No dose adjustment is suggested but caution is advised in patients with moderate hepatic impairment. INTELENCE has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is therefore not recommended (see sections 4.2 and 4.4).
Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance (potentially leading to increased exposure and alteration of the safety profile) for etravirine in HIV-1 infected patients with hepatitis B and/or hepatitis C virus co-infection. In view of the limited data available in hepatitis B and/or C co-infected patients, particular caution should be paid when INTELENCE is used in these patients (see sections 4.4 and 4.8).
The pharmacokinetics of etravirine have not been studied in patients with renal insufficiency. Results from a mass balance study with radioactive 14 C-etravirine showed that <1.2% of the administered dose of etravirine is excreted in the urine. No unchanged drug was detected in urine so the impact of renal impairment on etravirine elimination is expected to be minimal. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see section 4.2).
Study TMC114HIV3015 evaluated etravirine 200 mg twice daily in combination with other antiretroviral medicinal products in 15 pregnant women during the second and third trimesters of pregnancy and postpartum. The total etravirine exposure after intake of etravirine 200 mg twice daily as part of an antiretroviral regimen was generally higher during pregnancy compared with postpartum (see Table 9). The differences were less pronounced for unbound etravirine exposure. In women receiving etravirine 200 mg twice daily, higher mean values for Cmax, AUC12h and Cmin were observed during pregnancy compared to postpartum. During the 2nd and 3rd trimester of pregnancy mean values of these parameters were comparable.
Table 9. Pharmacokinetic results of total etravirine after administration of etravirine 200 mg twice daily as part of an antiretroviral regimen, during the 2nd trimester of pregnancy, the 3rd trimester of pregnancy, and postpartum:
| Pharmacokinetics of etravirine Mean ± SD (median) | Etravirine 200 mg Etravirine postpartum N=10 | Etravirine 200 mg twice daily 2nd trimester N=13 | Etravirine 200 mg twice daily 3rd trimester N=10a |
|---|---|---|---|
| Cmin, ng/mL | 269 ± 182 (284) | 383 ± 210 (346) | 349 ± 103 (371) |
| Cmax, ng/mL | 569 ± 261 (528) | 774 ± 300 (828) | 785 ± 238 (694) |
| AUC12h, h*ng/mL | 5.004 ± 2.521 (5.246) | 6.617 ± 2.766 (6.836) | 6.846 ± 1.482 (6.028) |
a n=9 for AUC12h
Each subject served as her own control, and with an intra-individual comparison, the total etravirine Cmin, Cmax and AUC12h values were 1.2-, 1.4- and 1.4-fold higher, respectively, during the 2nd trimester of pregnancy as compared to postpartum, and 1.1-, 1.4- and 1.2-fold higher, respectively, based during the 3rd trimester of pregnancy as compared to postpartum.
Animal toxicology studies have been conducted with etravirine in mice, rats, rabbits and dogs. In mice, the key target organs identified were the liver and the coagulation system. Haemorrhagic cardiomyopathy was only observed in male mice and was considered to be secondary to severe coagulopathy mediated via the vitamin K pathway. In the rat, the key target organs identified were the liver, the thyroid and the coagulation system. Exposure in mice was equivalent to human exposure while in rats it was below the clinical exposure at the recommended dose. In the dog, changes were observed in the liver and gall bladder at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg twice daily).
In a study conducted in rats, there were no effects on mating or fertility at exposure levels equivalent to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in rats and rabbits at exposures equivalent to those observed in humans at the recommended clinical dose. Etravirine had no effect on offspring development during lactation or post weaning at maternal exposures equivalent to those observed at the recommended clinical dose.
Etravirine was not carcinogenic in rats and in male mice. An increase in the incidences of hepatocellular adenomas and carcinomas were observed in female mice. The observed hepatocellular findings in female mice are generally considered to be rodent specific, associated with liver enzyme induction, and of limited relevance to humans. At the highest tested doses, the systemic exposures (based on AUC) to etravirine were 0.6-fold (mice) and between 0.2- and 0.7-fold (rats), relative to those observed in humans at the recommended therapeutic dose (200 mg twice daily). In vitro and in vivo studies with etravirine revealed no evidence of a mutagenic potential.
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