Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code: J05AG04.
Mechanism of action
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.

Antiviral activity in vitro
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.

Resistance
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.

Cross-resistance
Following virologic failure of an etravirine-containing regimen it is not recommended to treat patients with efavirenz and/or nevirapine.

Clinical efficacy and safety
Treatment-experienced adult patients
Pivotal studies
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
-     Design: randomised (1:1), double-blinded, placebo-controlled.
-     Treatment: etravirine vs. placebo, in addition to a background regimen (BR) including darunavir/ritonavir (DRV/rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF).
-     Main inclusion criteria:
• HIV-1 plasma viral load > 5,000 HIV-1 RNA copies/ml at screening
• 1 or more NNRTI resistance-associated mutations (RAMs) at screening or from prior genotypic analysis (i.e., archived resistance)
• 3 or more primary PI mutations at screening
• on a stable antiretroviral regimen for at least 8 weeks.
-     Stratification: Randomisation was stratified by the intended use of ENF in the BR, previous use of darunavir and screening viral load.
-     Virologic response was defined as achieving a confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml).

Summary of efficacy results

Table 3: DUET-1 and DUET-2 pooled 48-week data
Treatment etravirine + BR      Placebo + BR difference
N = 599             N = 604
(95% CI)
Baseline characteristics
Median plasma HIV-1 RNA          4.8 log10 copies/m   4.8 log10 copies/ l                  ml
Median CD4 cell count             99 x 106 cells/l    109 x 106 cells/l Outcomes
Confirmed undetectable viral load (< 50 HIV-1 RNA copies/ml)a n (%)
20.9%
Overall                         363 (60.6%)         240 (39.7%)
(15.3%; 26.4%)d
12.8%
De novo ENF                     109 (71.2%)          93 (58.5%)
(2.3%; 23.2%)f
23.9%
Not de novo ENF                 254 (57.0%)         147 (33.0%)
(17.6%; 30.3%)f
< 400 HIV-1 RNA copies/mla                                                     24.1% 428 (71.5%)         286 (47.4%) n (%)                                                                     (18.7%; 29.5%)d HIV-1 RNA log10 mean
-0.6 change from baseline                   -2.25               -1.49
(-0.8; -0.5)c
(log10 copies/ml)b
CD4 cell count mean change                                                     24.4 +98.2               +72.9 from baseline (x 106/l)b                                                   (10.4; 38.5)c 
Any AIDS defining illness                                                                               -3.9% 35 (5.8%)                  59 (9.8%) and/or death n (%)                                                                                 (-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
Proportion of subjects with HIV-1 RNA
< 50 copies/ml at week 48
Subgroups etravirine + BR               Placebo + BR
N = 599                      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) 

Baseline genotype or phenotype and virologic outcome analyses
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 arms etravirine RAMs*                                           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.

Exploratory head to head comparison with protease inhibitor in protease inhibitor naïve patients (trial TMC125-C227)
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.

Pregnancy and postpartum 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.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

The pharmacokinetic properties of etravirine have been evaluated in adult healthy subjects and in adult treatment-experienced HIV-1 infected patients. Exposure to etravirine was lower (35-50%) in HIV-1 infected patients than in healthy subjects.

Table 6: 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                                 4522 ± 4710 Median (Range)                                                  4380 (458 - 59084) C0h (ng/ml)
Geometric Mean ± Standard Deviation                                  297 ± 391 Median (Range)                                                     298 (2 - 4852) * 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 EC50 for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/ml.

Absorption
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.

Effect of food on absorption
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.

Distribution
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.

Biotransformation

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.

Elimination
After administration of a radiolabeled 14C-etravirine dose, 93.7% and 1.2% of the administered dose of 14
C-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.
 special populations
Children and adolescents
Treatment with INTELENCE in Israel is not approved in children and adolescents 
Elderly
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).

Gender
No significant pharmacokinetic differences have been observed between males and females. A limited number of females were included in the studies.

Race
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.

Hepatic impairment
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).


Hepatitis B and/or hepatitis C virus co-infection
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).

Renal impairment
The pharmacokinetics of etravirine have not been studied in patients with renal insufficiency. Results from a mass balance study with radioactive 14C-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).

Pregnancy and postpartum
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 7). 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 7: 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      Etravirine 200 mg       Etravirine 200 mg      Etravirine 200 mg of etravirine Mean         twice daily          twice daily 2nd       twice daily 3rd ± SD, (median)            postpartum               trimester             trimester N=10                    N=13                 N=10 a
Cmin, ng/mL                 269 ± 182              383 ± 210             349 ± 103 (284)                   (346)                 (371)
Cmax, ng/mL                 569 ± 261              774 ± 300             785 ± 238 (528)                   (828)                 (694)
AUC12h, h*ng /mL          5004 ± 2521            6617 ± 2766            6846 ± 1482 (5246)                  (6836)                (6028) 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.