Antiviral for systemic use, non-nucleoside reverse transcriptase inhibitor (NNRTI). ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Rilpivirine is a diarylpyrimidine NNRTI of human immunodeficiency virus type 1 (HIV-1). Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular deoxyribonucleic acid (DNA) polymerases α, β and γ.
Antiviral Activity in vitro:
Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50
value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Although rilpivirine demonstrated limited in vitro
activity against HIV-2 with EC50
values ranging from 2510-10,830 nM (920-3970 ng/mL), treatment of HIV-2 infection with Edurant is not recommended in the absence of clinical data.
Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50
values ranging from 0.07-1.01 nM (0.03-0.37 ng/mL) and group O primary isolates with EC50
values ranging from 2.88-8.45 nM (1.06-3.1 ng/mL).
In cell culture, rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The most commonly observed resistance-associated mutations that emerged included L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.
A biological cut-off (BCO) for rilpivirine was determined at the fold change in EC50
value (FC) of 3.7, on the basis of the analysis of the susceptibility of a large panel of HIV-1 wild-type recombinant clinical isolates.
In treatment-naive subjects For the resistance analysis, a broader definition of virologic failure was used than in the primary efficacy analysis. In the week 48 pooled resistance analysis from the Phase III trials, 62 (of a total of 72) virologic failures in the Edurant arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. In the trials, the presence of the mutations V90I and V189I, at baseline, did not affect response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination of E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses.
In the week 96 pooled resistance analysis, lower rates of virologic failure were observed in the second 48 weeks than in the first 48 weeks of treatment. From the week 48 to the week 96 analysis, 24 (3.5%) and 14 (2.1%) additional virologic failures occurred in the Edurant and efavirenz arm, respectively. Of these virologic failures, 9 out of 24 and 4 out of 14 were in subjects with a baseline viral load <100,000 copies/mL, respectively.
Considering all of the available in vitro
and in vivo
data in treatment-naive subjects, the following resistance-associated mutations, when present at baseline, may affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, and M230L. These rilpivirine resistance-associated mutations should only guide the use of Edurant in the treatment-naive population. These resistance-associated mutations were derived from in vivo
data involving treatment-naive subjects only and therefore cannot be used to predict the activity of rilpivirine in subjects who have virologically failed an antiretroviral-containing regimen.
As with other antiretroviral medicinal products, resistance testing should guide the use of Edurant.
Cross-Resistance: Site-Directed NNRTI Mutant Virus:
In a panel of 67 HIV-1 recombinant laboratory strains with 1 resistance-associated mutation at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity against 64 (96%) of these strains. The single resistance-associated mutations associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.
Recombinant Clinical Isolates:
Rilpivirine retained sensitivity (FC BCO) against 62% of 4786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.
Treatment-Naive HIV-1 Infected Patients:
In the week 96 pooled resistance analysis of the Phase III trials (ECHO and THRIVE), 42 out of 86 subjects with virologic failure on Edurant showed treatment-emergent resistance to rilpivirine (genotypic analysis). In these patients, phenotypic cross-resistance to other NNRTIs was noted as follows: Etravirine 32/42, efavirenz 30/42 and nevirapine 16/42. In patients with a baseline viral load ≤100,000 copies/mL, 9 out of 27 patients with virologic failure on Edurant showed treatment-emergent resistance to rilpivirine (genotypic analysis), with the following frequency of phenotypic cross-resistance: Etravirine 4/9, efavirenz 3/9, and nevirapine 1/9.
Effects on Electrocardiogram (ECG):
The effect of Edurant at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hrs at steady state. Edurant at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. When supratherapeutic doses of Edurant 75 mg once daily and 300 mg once daily were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) millisec, respectively. Steady-state administration of Edurant 75 mg once daily and 300 mg once daily resulted in a mean maximum plasma concentration (Cmax
) approximately 2.6- and 6.7-fold, respectively, higher than the mean steady-state Cmax
observed with the recommended 25 mg once daily dose of Edurant.
Clinical Efficacy and Safety: Treatment-Naive HIV-1 Infected Patients:
The evidence of efficacy of Edurant is based on the analyses of 96 week data from 2 randomised, double-blinded, active-controlled, Phase III trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE). The trials were identical in design, with the exception of the background regimen (BR). In the week 96 efficacy analysis, the virologic response rate [confirmed undetectable viral load (<50 HIV-1 RNA copies/mL)] was evaluated in patients receiving Edurant 25 mg once daily in addition to a BR versus patients receiving efavirenz 600 mg once daily in addition to a BR. Similar efficacy for Edurant was seen in each trial demonstrating noninferiority to efavirenz.
Antiretroviral treatment-naive HIV-1 infected patients were enrolled who had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated mutations. In ECHO, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In THRIVE, the BR consisted of 2 investigator-selected N(t)RTIs: Tenofovir disoproxil fumarate plus emtricitabine, or zidovudine plus lamivudine or abacavir plus lamivudine. In ECHO, randomisation was stratified by screening viral load. In THRIVE, randomisation was stratified by screening viral load and by N(t)RTI BR.
This analysis included 690 patients in ECHO and 678 patients in THRIVE who had completed 96 weeks of treatment or discontinued earlier.
In the pooled analysis for ECHO and THRIVE, demographics and baseline characteristics were balanced between the Edurant arm and the efavirenz arm. Table 1 displays selected baseline disease characteristics of the patients in the Edurant and efavirenz arms. (See Table 1.)
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Table 2 shows the results of the week 48 and the week 96 efficacy analysis for patients treated with Edurant and patients treated with efavirenz from the pooled data from the ECHO and THRIVE trials. The response rate (confirmed undetectable viral load <50 HIV-1 RNA copies/mL) at week 96 was comparable between the Edurant arm and the efavirenz arm. The incidence of virologic failure was higher in the Edurant arm than the efavirenz arm at week 96; however, most of the virologic failures occurred within the first 48 weeks of treatment. Discontinuations due to adverse events were higher in the efavirenz arm at week 96 than the Edurant arm. Most of these discontinuations occurred in the first 48 weeks of treatment. (See Table 2.)
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At week 96, the mean change from baseline in CD4+ cell count was +228 x 106
cells/L in the Edurant arm and +219 x 106
cells/L in the efavirenz arm in the pooled analysis of the ECHO and THRIVE trials [estimated treatment difference (95% CI): 11.3 (-6.8; 29.4)].
From the week 96 pooled resistance analysis, the resistance outcome for patients with protocol defined virological failure, and paired genotypes (baseline and failure) is shown in Table 3.
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For those patients failing therapy with Edurant and who developed resistance, cross-resistance to other approved NNRTIs (etravirine, efavirenz, nevirapine) was generally seen.
Study TMC278-C204 was a randomised, active-controlled, Phase IIb trial in antiretroviral treatment-naive HIV-1 infected adult patients consisting of 2 parts: An initial partially blinded dose-finding part [(Edurant) doses blinded] up to 96 weeks, followed by a long-term, open label part. In the open label part of the trial, patients originally randomised to 1 of the 3 doses were all treated with Edurant 25 mg once daily in addition to a BR, once the dose for the Phase III studies was selected. Patients in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: Zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1 infected treatment-naive adult patients who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received 2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI resistance-associated mutations.
At 96 weeks, the proportion of patients with <50 HIV-1 RNA copies/mL receiving Edurant 25 mg (N=93) compared to patients receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 x 106
cells/L in patients receiving Edurant 25 mg and 160 x 106
cells/L in patients receiving efavirenz.
Of those patients who were responders at week 96, 74% of patients receiving Edurant remained with undetectable viral load (<50 HIV-1 RNA copies/mL) at week 240 compared to 81% of patients receiving efavirenz. There were no safety concerns identified in the week 240 analyses.
The European Medicines Agency has deferred the obligation to submit the results of studies with Edurant in ≥1 subsets of the paediatric population in the treatment of HIV-1 infection in ARV-naïve patients (see Dosage & Administration).
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naive HIV-1 infected patients. Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hrs. The absolute bioavailability of Edurant is unknown.
Effect of Food on Absorption:
The exposure to rilpivirine was approximately 40% lower when Edurant was taken in a fasted condition as compared to a normal caloric meal (533 kCal) or high-fat high-caloric meal (928 kCal). When Edurant was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. Edurant must be taken with a meal to obtain optimal absorption. Taking Edurant in fasted condition or with only a nutritional drink may result in decreased plasma concentrations of rilpivirine, which could potentially reduce the therapeutic effect of Edurant (see Dosage & Administration).
Rilpivirine is approximately 99.7% bound to plasma proteins in vitro
, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (eg, cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.
Biotransformation: In vitro
experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P-450 (CYP) 3A system.
The terminal elimination half-life of rilpivirine is approximately 45 hrs. After single dose oral administration of 14
C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
Additional Information on Special Populations: Paediatric Population:
The pharmacokinetics of rilpivirine in pediatric patients are under investigation. Dosing recommendations for pediatric patients cannot be made due to insufficient data.
Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics are not different across the age range (18-78 years) evaluated, with only 3 subjects ≥65 years. No dose adjustment of Edurant is required in elderly patients. It should be used with caution in this population (see Dosage & Administration).
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.
Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.
Rilpivirine is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepatic impairment.
No dose adjustment is suggested but caution is advised in patients with moderate hepatic impairment. Edurant has not been studied in patients with severe hepatic impairment (Child-Pugh score C). Therefore, Edurant is not recommended in patients with severe hepatic impairment (see Dosage & Administration).
Hepatitis B and/or Hepatitis C Virus Co-Infection:
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.
The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild or moderate renal impairment. In patients with severe renal impairment or end-stage renal disease, Edurant should be used with caution, as plasma concentrations may be increased due to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. In patients with severe renal impairment or end-stage renal disease, the combination of Edurant with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Repeated-Dose Toxicity:
Liver toxicity associated with liver enzyme induction was observed in rodents. In dogs, cholestasis-like effects were noted.
Reproductive Toxicology Studies:
Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function. There was no teratogenicity with rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Carcinogenesis and Mutagenesis:
Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily). In rats, there were no drug-related neoplasms. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific.
Rilpivirine has tested negative in the absence and presence of a metabolic activation system in the in vitro
Ames reverse mutation assay and the in vitro
clastogenicity mouse lymphoma assay. Rilpivirine did not induce chromosomal damage in the in vivo
micronucleus test in mice.