Intelence Mechanism of Action

Pharmacology: Mechanism of Action: Etravirine is an antiviral drug [see Microbiology: Mechanism of Action as follows].
Pharmacodynamics: Effects on Electrocardiogram: In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE 200 mg twice daily, INTELENCE 400 mg once daily, placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg twice daily and -1.0 ms (2.5 ms) for 400 mg once daily dosing regimens.
Clinical Studies: Treatment-Experienced Subjects: The clinical efficacy of INTELENCE is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2). These trials are identical in design and the following results are pooled data from the two trials.
TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of INTELENCE in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected patients with plasma HIV-1 RNA greater than 5000 copies per mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis, and 3 or more of the following primary PI mutations at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies per mL at Week 48.
All study subjects received DRV/rtv as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of INTELENCE-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF.
In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the INTELENCE arm and the placebo arm. Table 1 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE and placebo arms. (See Table 1.)

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Efficacy at Week 48 for subjects in the INTELENCE and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 2. (See Table 2.)

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At Week 48, 70.8% of INTELENCE-treated subjects achieved HIV-1 RNA less than 400 copies per mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log₁₀ copies per mL for INTELENCE-treated subjects and -1.46 log₁₀ copies per mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE-treated subjects was 96 cells per mm³ and 68 cells per mm³ for placebo-treated subjects.
Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL. Of the study population using ENF de novo, 67.3% of INTELENCE-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL.
Treatment-emergent CDC category C events occurred in 4% of INTELENCE-treated subjects and 8.4% of placebo-treated subjects.
Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected patients with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to INTELENCE (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. INTELENCE-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE as compared to the control PI-treated subjects.
Pharmacokinetics: Pharmacokinetics in Adults: The pharmacokinetic properties of INTELENCE were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects than in healthy subjects. (See Table 3.)

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Absorption and Bioavailability: Following oral administration, etravirine was absorbed with a T_max of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE is unknown.
In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.
Effects of Food on Oral Absorption: The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE was administered under fasting conditions, as compared to when INTELENCE was administered following a meal. Therefore, INTELENCE should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). [See Dosage & Administration.]
Distribution: Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 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.
Metabolism: In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.
Elimination: After single dose oral administration of 800 mg ¹⁴C-etravirine, 93.7% and 1.2% of the administered dose of ¹⁴C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.
Special Populations: Hepatic Impairment: Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated.
Hepatitis B and/or Hepatitis C Virus Co-infection: Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of INTELENCE [see Clinical Trials Experience: Patients co-infected with hepatitis B and/or hepatitis C virus under Adverse Reactions], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.
Renal Impairment: The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with ¹⁴C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Gender: No significant pharmacokinetic differences have been observed between males and females.
Race: Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.
Geriatric Patients: Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Elderly under Precautions].
Pediatric Patients: The pharmacokinetics of etravirine in pediatric patients have not been evaluated. Dosing recommendations for pediatric patients cannot be made due to insufficient data.
Drug Interactions [see also Interactions]: Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE.
Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s).
Drug interaction studies were performed with INTELENCE and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, C_max, and C_min values of etravirine are summarized in Table 4 (effect of other drugs on INTELENCE). The effect of co-administration of INTELENCE on the AUC, C_max, and C_min values of other drugs are summarized in Table 5 (effect of INTELENCE on other drugs). For information regarding clinical recommendations, see Interactions. (See Tables 4 and 5.)

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Toxicology: Nonclinical Toxicology: Carcinogenesis: Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg per kg were administered to mice and doses of 70, 200 and 600 mg per kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50 to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg per day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2-0.7-fold (rats).
Mutagenesis: Etravirine 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 micronucleus test in mice.
Impairment of Fertility: No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg per kg per day, resulting in systemic drug exposure up to the recommended human dose (400 mg per day).
Microbiology: 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. Etravirine does not inhibit the human DNA polymerases α, β, and γ.
Antiviral Activity in Cell Culture: Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC₅₀ values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC₅₀ values ranging from 0.29 to 1.65 nM and EC₅₀ values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs: the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the fusion inhibitor enfuvirtide; the integrase strand transfer inhibitor raltegravir and the CCR5 co-receptor antagonist maraviroc.
Resistance: In Cell Culture: Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.
In Treatment-Experienced Subjects: In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the INTELENCE-containing regimen were V179F, V179I, and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with INTELENCE in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance associated substitutions which emerged on etravirine treatment in less than 10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190S/C, N348I and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.
Cross-Resistance: Site-Directed NNRTI Mutant Virus: Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility greater than 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC₅₀ value) and Y181V (17-fold change in EC₅₀ value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change greater than 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).
Clinical Isolates: Etravirine retained a fold-change less than or equal to 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125-C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change greater than 3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Of subjects who received etravirine and were virologic failures in TMC125-C206 and TMC125-C216, 90%, 84%, and 96% of viral isolates obtained at the time of treatment failure were resistant to delavirdine, efavirenz, and nevirapine, respectively. Therefore, cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen for the virologic failure isolates.
Treatment-naïve HIV-1-infected subjects in the Phase 3 trials for EDURANT (rilpivirine): There are currently no clinical data available on the use of etravirine in subjects who experienced virologic failure on a rilpivirine-containing regimen. However, in the rilpivirine adult clinical development program, there was evidence of phenotypic cross-resistance between rilpivirine and etravirine. In the pooled analyses of the Phase 3 clinical trials for rilpivirine, 38 rilpivirine virologic failure subjects had evidence of HIV-1 strains with genotypic and phenotypic resistance to rilpivirine. Of these subjects, 89% (34 subjects) of virologic failure isolates were cross-resistant to etravirine based on phenotype data. Consequently, it can be inferred that cross-resistance to etravirine is likely after virologic failure and development of rilpivirine resistance. Refer to the prescribing information for EDURANT (rilpivirine) for further information.
Baseline Genotype/Phenotype and Virologic Outcome Analyses: In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with a decreased virologic response to etravirine. Additional substitutions associated with a decreased virologic response to etravirine when in the presence of 3 or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the INTELENCE arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load less than 50 plasma HIV RNA copies/mL at Week 48) (Table 6). (See Table 6.)

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Response rates assessed by baseline etravirine phenotype are shown in Table 7. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for INTELENCE. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients. (See Table 7.)

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The proportion of virologic responders (viral load less than 50 HIV-1 RNA copies per mL) by the phenotypic susceptibility score (PSS) of the background therapy, including enfuvirtide, is shown in Table 8. (See Table 8.)

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