Non-nucleoside reverse transcriptase inhibitor (NNRTI). ATC Code:
Pharmacology: Pharmacodynamics: 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- 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 effective concentration (EC50
) values ranging from 0.9-5.5 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 0.3-1.7 nM and from 11.5-21.7 nM, respectively. Although etravirine demonstrates in vitro
activity against wild type HIV-2 with EC50
values ranging from 5.7-7.2 micromol, 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 NNRTIs and/or protease inhibitors (PIs). In addition, etravirine demonstrates a fold change (FC) in EC50
≤3 against 60% of 6171 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) 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 Intelence-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 trials conducted with Intelence in HIV-1-infected patients, the most common emerged mutations are 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.
Clinical Experience: Treatment-Experienced Patients: Pivotal Studies:
The evidence of efficacy of Intelence is based on the analyses of 48-week data from 2 ongoing phase III trials DUET-1 and DUET-2. These trials were identical in design and similar efficacy for Intelence was seen in each trial. The results as follows are pooled data from the 2 trials.
Trial Characteristics: Design:
Randomised (1:1), double-blinded, placebo-controlled.
Treatment: Intelence versus placebo, in addition to a background regimen including darunavir/ritonavir (DRV/rtv), investigator-selected N(t)RTIs and optional enfuvirtide (ENF).
Main Inclusion Criteria:
HIV-1 plasma viral load >5000 HIV-1 RNA copies/mL at screening; ≥1 NNRTI RAMs at screening or from prior genotypic analysis (ie, archived resistance); ≥3 primary PI mutations at screening; on a stable antiretrovital regimen for at least 8 weeks.
Randomisation was stratified by the intended use of ENF in the background regimen (BR), previous use of darunavir and screening viral load.
Virologic response was defined as achieving a confirmed undetecteable viral load (<50 HIV-1 RNA copies/mL).
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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 Intelence 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 1. (See Table 1.)
Significantly fewer patients in the Intelence arm reached a clinical endpoint (AIDS-defining illness 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 2. (See Table 2.)
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Baseline Genotype or Phenotype and Virologic Outcome Analysis:
In DUET-1 and DUET-2, the presence at baseline of ≥3 of the following mutations: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S (Intelence RAMs) was associated with a decreased virologic response to Intelence (see Table 3). 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.
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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 Intelence. Furthermore, the presence of this mutation did not affect the response in the Intelence 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 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 selected patient populations in DUET-1 and DUET-2 and are not meant to represent definitive clinical susceptibility breakpoints for Intelence.
Exploratory Head to Head Comparison with Protease Inhibitor in Protease-Inhibitor Naive Patients (Trial TMC125-C227):
TMC125-C227 was an exploratory, randomised, active-controlled open-label trial, which investigated the efficacy and safety of Intelence in a treatment regimen, which is not approved under the current indication. In the TMC125-C227 study, Intelence (N=59) was administered with 2 investigator-selected NRTIs (ie, 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-naive, 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 Intelence arm (-1.4 log10
copies/mL from baseline; n=40). This difference between treatment arms was statistically significant.
Based on these trial results, Intelence 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.
Intelence has been authorised under a so-called "conditional approval" scheme. This means that further evidence on Intelence is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.
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 slightly lower in HIV-1 infected patients than in healthy subjects.
An IV formulation of etravirine is unavailable; thus, the absolute bioavailability of Intelence is unknown. After oral administration with food, the maximum plasma concentration of etravirine is generally achieved within 4 hrs. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that are known to increase gastric pH.
Effect of Food on Absorption:
The exposure to etravirine is similar when taken following a standard normal caloric meal (561 kcal) or high-fat high-caloric meal (1160 kcal). When compared to administration following a standard normal caloric meal, exposures decreased when etravirine was taken before a standard normal caloric meal (17%), following a croissant (20%) or fasted (51%). Therefore, to achieve optimal exposure, 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 (eg, cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Metabolism: In vitro
experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes oxidative metabolism by the hepatic cytochrome P-450 (CYP) 3A system and, to a lesser extent, by the CYP2C family, followed by glucuronidation.
After administration of a radiolabeled 14
C-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 81.2-86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The terminal elimination half-life of etravirine was approximately 30-40 hrs.
Special Populations: Children and Adolescents:
The pharmacokinetics of etravirine in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see Dosage & Administration).
Population pharmacokinetic analysis in HIV-infected patients showed that etravirine pharmacokinetics are not considerably different in the age range (18-77 years) evaluated (see Dosage & Administration and Precautions).
No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in the studies.
Population pharmacokinetic analysis of etravirine in HIV-infected patients indicated that race had no apparent effect on the exposure to etravirine.
Etravirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild (Child-Pugh score A) hepatic impairment to 8 matched controls and 8 patients with moderate (Child-Pugh score 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. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Intelence has not been studied in patients with severe hepatic impairment (Child-Pugh score C) (see Dosage & Administration and Precautions).
Hepatitis B and/or Hepatitis C Virus Co-infection:
Population pharmacokinetic analysis of the DUET-1 and DUET-2 trials showed reduced clearance for Intelence in HIV-1-infected patients with hepatitis B and/or C virus co-infection. Based upon the safety profile (see Adverse Reactions), no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.
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 Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data:
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. This is considered not relevant to humans. In rats, the key target organs identified were the liver, 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 dogs, changes in the liver and gallbladder were seen at exposures approximately 8-fold higher than human exposure observed at the recommended dose (200 mg bd).
In a study conducted in rats, there were no effects on mating or fertility with Intelence treatment up to 500 mg/kg/day and exposure levels equivalent to those in humans at the clinically recommended dose. There was no teratogenicity with etravirine in rats (1000 mg/kg) and rabbits (375 mg/kg) at exposures equivalent to those observed in humans at the recommended clinical dose. In a pre- and postnatal development assessment in rats, etravirine had no effect on offspring development during lactation or post-weaning when the mother was dosed up to 500 mg/kg and at exposures equivalent to those observed at the recommended clinical dose.
Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 50 mg/kg, 200 mg/kg and 400 mg/kg were administered to mice and doses of 70 mg/kg, 200 mg/kg and 600 mg/kg were administered to rats. 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. Administration of etravirine did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. 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 bd).
Etravirine has tested negative in the in vitro
Ames reverse mutation assay, in vitro
chromosomal aberration assay in human lymphocyte and in vitro
clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo
micronucleous test in mice.