Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use, non-nucleoside reverse transcriptase inhibitors, ATC code: J05AG05.

Mechanism of action

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular 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 2,510 to 10,830 nM (920 to 3,970 ng/ml), treatment of HIV-2 infection with rilpivirine 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 to 1.01 nM (0.03 to 0.37 ng/ml) and group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/ml).

Resistance

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.

Resistance to rilpivirine was determined as a fold change in EC50 value (FC) above the biological cut-off (BCO) of the assay.

In treatment-naïve adult 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 rilpivirine 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 rilpivirine 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.



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In treatment-naïve adolescent subjects
In the week 240 resistance analysis of the TMC278-C213 trial, rilpivirine resistance-associated mutations (RAMs) were observed in 46.7% (7/15) of subjects with virologic failure and post-baseline genotypic data. All subjects with rilpivirine RAMs also had at least 1 treatment-emergent NRTI RAM at the last post-baseline time point with genotypic data.

Considering all of the available in vitro and in vivo data in treatment-naïve 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-naïve population. These resistance-associated mutations were derived from in vivo data involving treatment-naïve 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 one 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 4,786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.

Treatment-naïve HIV-1 infected adult 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 rilpivirine 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 rilpivirine 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

The effect of rilpivirine 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 hours 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 75 mg once daily and 300 mg once daily of rilpivirine 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) ms, respectively.
Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 25 mg once daily dose of rilpivirine.



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Clinical efficacy and safety

Treatment-naïve HIV-1 infected adult patients
The evidence of efficacy of rilpivirine is based on the analysis 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 rilpivirine 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 rilpivirine was seen in each trial demonstrating non-inferiority to efavirenz.

Antiretroviral treatment-naïve HIV-1 infected patients were enrolled who had a plasma HIV-1 RNA ≥ 5,000 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 rilpivirine arm and the efavirenz arm. Table 3 displays selected baseline disease characteristics of the patients in the rilpivirine and efavirenz arms.

Table 3:       Baseline disease characteristics of antiretroviral treatment-naïve HIV-1 infected adult subjects in the ECHO and THRIVE trials (pooled analysis)
Pooled data from the ECHO and THRIVE trials
Rilpivirine + BR               Efavirenz + BR
N=686                         N=682
Baseline disease characteristics
Median baseline plasma HIV-1 RNA (range),                    5.0                            5.0 log10 copies/ml                                             (2-7)                          (3-7) Median baseline CD4+ cell count (range),                     249                            260 x 106 cells/l                                              (1-888)                       (1-1,137) Percentage of subjects with: hepatitis B/C virus co-infection                          7.3%                          9.5% Percentage of patients with the following background regimens: tenofovir disoproxil fumarate plus                       80.2%                         80.1% emtricitabine zidovudine plus lamivudine                               14.7%                         15.1% abacavir plus lamivudine                                  5.1%                         4.8% BR=background regimen


Table 4 below shows the results of the week 48 and the week 96 efficacy analysis for patients treated with rilpivirine 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 rilpivirine arm and the efavirenz arm. The incidence of virologic failure was higher in the rilpivirine 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 rilpivirine arm. Most of these discontinuations occurred in the first 48 weeks of treatment.



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Table 4:      Virologic outcome in adult subjects in the ECHO and THRIVE trials (pooled data in the week 48 (primary) and week 96 analysis; ITT-TLOVR*) Outcome in the week 48 analysis        Outcome in the week 96 analysis Rilpivirine Efavirenz Observed Rilpivirine Efavirenz Observed
+ BR         + BR      difference      + BR        + BR      difference N=686        N=682      (95% CI) ±     N=686        N=682     (95% CI) ± Response (confirmed                84.3%        82.3%          2.0        77.6%       77.6%           0 < 50 HIV-1 RNA                  (578/686) (561/682) (-2.0; 6.0)        (532/686) (529/682) (-4.4; 4.4) copies/ml)§#
Non-response
Virologic failure†
Overall                          9.0%        4.8%          ND          11.5%        5.9%         ND (62/686)     (33/682)                  (79/686)    (40/682)
≤ 100,000                        3.8%        3.3%          ND           5.7%        3.6%         ND (14/368)     (11/330)                  (21/368)    (12/329)
> 100,000                       15.1%        6.3%          ND          18.2%        7.9%         ND (48/318)     (22/352)                  (58/318)    (28/353)
Death                            0.1%        0.4%          ND           0.1%        0.9%         ND (1/686)      (3/682)                   (1/686)     (6/682)
Discontinued due to              2.0%        6.7%          ND           3.8%        7.6%         ND adverse event (AE)            (14/686)     (46/682)                  (26/682)    (52/682) Discontinued for non-AE          4.5%        5.7%          ND           7.0%        8.1%         ND reason¶                       (31/686)     (39/682)                  (48/682)    (55/682) Response by subcategory
By background NRTI
Tenofovir/emtricitabine         83.5%        82.4%         1.0         76.9%       77.3%        -0.4% (459/550) (450/546) (-3.4; 5.5)        (423/550) (422/546) (-5.4; 4.6) Zidovudine/lamivudine           87.1%        80.6%          6.5        81.2%       76.7%        4.5% (88/101)     (83/103) (-3.6; 16.7)     (82/101)    (79/103) (-6.8; 15.7) Abacavir/lamivudine             88.6%        84.8%          3.7        77.1%       84.8%        -7.7% (31/35)      (28/33) (-12.7; 20.1)     (27/35)     (28/33) (-26.7; 11.3) By baseline viral load (copies/ml)
≤ 100,000                       90.2%        83.6%          6.6        84.0%       79.9%         4.0 (332/368) (276/330) (1.6; 11.5)        (309/368) (263/329) (-1.7; 9.7) > 100,000                       77.4%        81.0%         -3.6        70.1%       75.4%         -5.2 (246/318) (285/352) (-9.8; 2.5)        (223/318) (266/353) (-12.0;1.5) By baseline CD4 count (× 106 cells/l)
< 50                            58.8%        80.6%        -21.7        55.9%       69.4%        -13.6 (20/34)      (29/36)   (-43.0; -0.5)   (19/34)     (25/36)    (-36.4; 9.3) ≥ 50-< 200                      80.4%        81.7%         -1.3        71.1%       74.9%         -3.7 (156/194) (143/175) (-9.3; 6.7)        (138/194) (131/175) (-12.8; 5.4) ≥ 200-< 350                     86.9%        82.4%          4.5        80.5%       79.5%         1.0 (272/313) (253/307) (-1.2; 10.2) (252/313) (244/307) (-5.3; 7.3)
≥ 350                           90.3%        82.9%          7.4        85.4%       78.7%         6.8 (130/144) (136/164) (-0.3; 15.0) (123/144) (129/164) (-1.9; 15.4)
BR=background regimen; CI=confidence interval; N=number of subjects per treatment group; ND=not determined.
* Intent-to-treat time to loss of virologic response.
±
Based on normal approximation.
§
Subjects achieved virologic response (two consecutive viral loads < 50 copies/ml) and maintained it through week 48/96.
#
Predicted difference of response rates (95% CI) for the week 48 analysis: 1.6% (-2.2%; 5.3%) and for the week 96 analysis: -0.4% (-4.6%; 3.8%); both p-value < 0.0001 (non-inferiority at 12% margin) from logistic regression model, including stratification factors and study.
†
Virologic failure in pooled efficacy analysis: includes subjects who were rebounder (confirmed viral load ≥ 50 copies/ml after being responder) or who were never suppressed (no confirmed viral load < 50 copies/ml, either ongoing or discontinued due to lack or loss of efficacy).
¶ e.g. lost to follow-up, non-compliance, withdrew consent.


At week 96, the mean change from baseline in CD4+ cell count was +228 × 106 cells/l in the rilpivirine arm and +219 × 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)].


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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 5.

Table 5:          Resistance outcome by background NRTI regimen used (pooled data from the ECHO and THRIVE trials in the week 96 resistance analysis) tenofovir/               zidovudine/                  abacavir/                      All* emtricitabine               lamivudine                  lamivudine
Rilpivirine-treated
Resistance# to                         6.9 (38/550)               3.0 (3/101)                  8.6 (3/35)                6.4 (44/686) emtricitabine/lamivudine
% (n/N)
Resistance to rilpivirine              6.5 (36/550)               3.0 (3/101)                  8.6 (3/35)                6.1 (42/686) % (n/N)
Efavirenz-treated
Resistance to                           1.1 (6/546)               1.9 (2/103)                  3.0 (1/33)                 1.3 (9/682) emtricitabine/lamivudine
% (n/N)
Resistance to efavirenz                2.4 (13/546)               2.9 (3/103)                  3.0 (1/33)                2.5 (17/682) % (n/N)
* The number of patients with virologic failure and paired genotypes (baseline and failure) were 71, 11, and 4 for rilpivirine and 30, 10, and 2 for efavirenz, for the tenofovir/emtricitabine, zidovudine/lamivudine, and abacavir/lamivudine regimens, respectively.
#
Resistance was defined as the emergence of any resistance-associated mutation at failure.


For those patients failing therapy with rilpivirine and who developed resistance to rilpivirine, 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-naïve HIV-1 infected adult patients consisting of 2 parts: an initial partially blinded dose-finding part [(rilpivirine) 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 one of the three doses of rilpivirine were all treated with rilpivirine 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-naïve adult patients who had a plasma HIV-1 RNA ≥ 5,000 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 rilpivirine 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 × 106 cells/l in patients receiving rilpivirine 25 mg and 160 × 106 cells/l in patients receiving efavirenz.

Of those patients who were responders at week 96, 74% of patients receiving rilpivirine 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.

Paediatric population

The pharmacokinetics, safety, tolerability and efficacy of rilpivirine 25 mg once daily, in combination with an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278-C213, a single-arm, open-label Phase II trial in antiretroviral treatment-naïve HIV-1 infected adolescent subjects weighing at least 32 kg. This analysis included 36 patients who had completed at least 48 weeks of treatment or discontinued earlier.



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The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 55.6% female, 88.9% Black and 11.1% Asian. The median baseline plasma HIV-1 RNA was 4.8 log10 copies per ml, and the median baseline CD4+ cell count was 414 × 106 cells/l (range: 25 to 983 × 106 cells/l).

Table 6 summarizes the week 48 and week 240 virologic outcome results for trial TMC278- C213. Six subjects discontinued due to virological failure up to week 48 and 3 subjects discontinued beyond week 48. One subject discontinued due to an adverse event at week 48, and no additional subjects discontinued due to adverse events in the week 240 analysis.

Table 6:     Virologic outcome in adolescent subjects in the TMC278-C213 trial – week 48 and week 240 analysis; ITT-TLOVR*
Week 48                           Week 240
N=36                               N=32
Response (confirmed < 50 HIV-1                  72.2%                              43.8% RNA copies/ml)§                                 (26/36)                            (14/32) 78.6%                                48%
≤ 100,000                                    (22/28)                            (12/25) 50%                               28.6%
> 100,000
(4/8)                              (2/7)
Non-response
Virologic failure±
22.2%                               50%
Overall
(8/36)                            (16/32)
17.9%                               48%
≤ 100,000
(5/28)                            (12/25)
37.5%                              57.1%
> 100,000
(3/8)                              (4/7)
Increase in CD4+ cell count                           6
201.2 × 10 cells/l                113.6 × 106 cells/l
(mean)
N=number of subjects per treatment group.
* Intent-to-treat time to loss of virologic response.
§
Subjects achieved virologic response (two consecutive viral loads < 50 copies/ml) and maintained it through week 48 and week 240.
±
Virologic failure in efficacy analysis: includes subjects who were rebounder (confirmed viral load ≥ 50 copies/ml after being responder) or who were never suppressed (no confirmed viral load < 50 copies/ml, either ongoing or discontinued due to lack or loss of efficacy).

Pregnancy
Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks).
The virologic response was generally preserved throughout the study: of the 12 subjects that completed the study, 10 subjects were suppressed at the end of the study; in the other 2 subjects an increase in viral load was observed only postpartum, for at least 1 subject due to suspected suboptimal adherence. No mother to child transmission occurred in all 10 infants born to the mothers who completed the trial and for whom the HIV status was available.
Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults (see sections 4.2, 4.4 and 5.2).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in antiretroviral treatment-naïve HIV-1 infected patients 12 years of age and older.
Exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy Edurant_SPC_04-2024
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subjects.

Absorption

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours. 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 section 4.2).

Distribution

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin.
The distribution of rilpivirine into compartments other than plasma (e.g., 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 P450 (CYP) 3A system.

Elimination

The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oral administration of 14C-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 (less than 18 years of age)
The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1 infected adolescent subjects receiving EDURANT 25 mg once daily were comparable to those in treatment-naïve HIV-1 infected adults receiving EDURANT 25 mg once daily. There was no impact of body weight on rilpivirine pharmacokinetics in paediatric subjects in trial TMC278-C213 (33 to 93 kg), similar to what was observed in adults.

The pharmacokinetics of rilpivirine in paediatric patients less than 12 years of age are under investigation. Dosing recommendations for paediatric patients less than 12 years of age cannot be made due to insufficient data (see section 4.2).

Older people
Population pharmacokinetic analysis in HIV infected patients showed that rilpivirine pharmacokinetics are not different across the age range (18 to 78 years) evaluated, with only 3 subjects aged 65 years or older. No dose adjustment of EDURANT is required in older patients.
EDURANT should be used with caution in this population (see section 4.2).

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Gender
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.

Race
Population pharmacokinetic analysis of rilpivirine in HIV infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.

Hepatic impairment
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 section 4.2).

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.

Renal impairment
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 section 4.2).

Pregnancy and Postpartum
The exposure to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was lower during pregnancy (similar for the 2 nd and 3rd trimester) compared with postpartum (see table 7). The decrease in unbound (ie, active) rilpivirine pharmacokinetic parameters during pregnancy compared to postpartum was less pronounced than for total rilpivirine.

In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intra- individual values for total rilpivirine Cmax, AUC24h and Cmin values were, respectively, 21%, 29% and 35% lower as compared to postpartum; during the 3rd trimester of pregnancy,
Cmax, AUC24h and Cmin values were, respectively, 20%, 31% and 42% lower as compared to postpartum.

Table 7:    Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
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Pharmacokinetics of total                Postpartum            2nd Trimester          3rd Trimester rilpivirine                             (6-12 Weeks)           of pregnancy           of pregnancy (mean ± SD, tmax: median [range])           (n=11)                 (n=15)                 (n=13) Cmin, ng/ml                               84.0 ± 58.8           54.3 ± 25.8            52.9 ± 24.4 Cmax, ng/ml                                167 ± 101             121 ± 45.9             123 ± 47.5 tmax, h                               4.00 (2.03-25.08)       4.00 (1.00-9.00)      4.00 (2.00-24.93) AUC24h, ng.h/ml                          2714 ± 1535            1792 ± 711             1762 ± 662