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 non-nucleoside reverse-transcriptase inhibitor (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

Considering all of the available in vitro data and in vivo data generated with oral rilpivirine in previously untreated patients, 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, M230L, and the combination of L100I and K103N.

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.

Virologically suppressed patients:
The number of subjects who met confirmed virologic failure (CVF) criteria was low across the pooled Phase 3 studies ATLAS and FLAIR. There were 7 CVFs on rilpivirine plus cabotegravir (7/591, 1.2%) and 7 CVFs on current antiretroviral regimen (7/591, 1.2%) through week 48. In the rilpivirine plus cabotegravir group in the pooled analysis, 5/591 (0.8%) subjects had resistance development: 5/591 (0.8%) and 4/591 (0.7%) with resistance-associated mutations to rilpivirine (K101E [n=1], E138A/E/K/T [n=1], E138A [n=1], or E138K [n=2]) and/or cabotegravir (G140R [n=1], Q148R [n=2], or N155H [n=1]), respectively. The 4 CVFs on cabotegravir plus rilpivirine in FLAIR had HIV-1 subtype A1 (n=3) or AG (n=1). One CVF in FLAIR never received an injection. The 3 CVFs on cabotegravir plus rilpivirine in ATLAS had HIV-1 subtype A, A1, or AG. In 2 of these 3 CVFs the rilpivirine resistance-associated mutations observed at failure were also observed at baseline in PBMC HIV-1 DNA.
In the ATLAS-2M study 10 subjects met CVF criteria through week 48: 8/522 (1.5%) in the Q8W arm and 2/523 (0.4%) in the Q4W arm. In the Q8W group 5/522 (1.0%) had resistance development: 4/522 (0.8%) and 5/522 (1.0%) with resistance-associated mutations to rilpivirine (E138A [n=1], E138K [n=1], K101E [n=2], or Y188L [n=1]) and/or cabotegravir (Q148R [n=3] or N155H [n=4]), respectively. In the Q4W group 2/523 (0.4%) had resistance development: 1/523 (0.2%) and 2/523 (0.4%) had rilpivirine (K101E [n=1], M230L [n=1]) and/or cabotegravir (E138K [n=1], Q148R [n=1], or N155H [n=1]) resistance-associated mutations, respectively. At baseline in the Q8W arm, 5 subjectshad rilpivirine resistance-associated mutations and 1 of those subjects carried a cabotegravir resistance-associated mutation. Neither subject in the Q4W arm had any rilpivirine or cabotegravir resistance-assocaiated mutation at baseline. The 10 CVFs on cabotegravir plus rilpivirine in ATLAS-2M had HIV-1 subtype A (n=1), A1 (n=2), B (n=4), C (n=2), or Complex (n=1).

Cross-resistance

Site-directed NNRTI mutant virus
In a panel of 67 HIV-1 recombinant laboratory strains with one 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 mutation 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 (fold change ≤ biological cut-off) against 62% of 4,786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.

Virologically suppressed patients
In the week 48 analysis of the Phase 3 studies ATLAS and FLAIR, 5/7 CVFs had phenotypic resistance against rilpivirine at failure. Among these 5 patients, phenotypic cross-resistance was observed against efavirenz (n=4), etravirine (n=3), and nevirapine (n=4).

Effects on electrocardiogram

No effect on QTcF interval was shown for oral rilpivirine at the recommended dose of 25 mg once daily 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. Plasma rilpivirine concentrations after REKAMBYS injections are comparable to those achieved with oral rilpivirine at dose of 25 mg qd. REKAMBYS at the recommended dose of 600 mg monthly or 900 mg every 2 months is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of oral 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 oral rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 4.4-fold and 11.6-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 600 mg once monthly dose of REKAMBYS. Steady state administration of oral rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmax approximately 4.1-fold and 10.7-fold, respectively, higher than the mean steady state Cmax observed with the recommended 900 mg every 2 months dose of REKAMBYS.

Clinical efficacy and safety

Every 1 month dosing
The efficacy of REKAMBYS plus cabotegravir injection has been evaluated in two Phase 3 randomised, multicentre, active-controlled, parallel-arm, open-label, non-inferiority studies, FLAIR (201584) and ATLAS (201585). The primary analysis was conducted after all subjects completed their week 48 visit or discontinued the study prematurely.

Patients virologically suppressed (on prior dolutegravir-based regimen for 20 weeks) In FLAIR, 629 HIV-1-infected, antiretroviral treatment (ART)-naive subjects received a dolutegravir integrase strand transfer inhibitor (INI) containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir + 2 other nucleoside reverse transcriptase inhibitors if subjects were HLA-B*5701 positive). Subjects who were virologically suppressed (HIV-1 RNA < 50 copies per mL, n=566) were then randomised (1:1) to receive either a rilpivirine plus cabotegravir regimen or remain on the CAR. Subjects randomised to receive the rilpivirine plus cabotegravir regimen, initiated treatment with oral lead-in dosing with a cabotegravir (30 mg) tablet plus a rilpivirine (25 mg) tablet once daily for at least 4 weeks, followed by treatment with cabotegravir injection (month 1: 600 mg, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection), monthly, for up to 96 weeks.
Patients virologically suppressed (stable on prior ART for at least 6 months) In ATLAS, 616 HIV-1-infected, ART-experienced, virologically-suppressed (for at least 6 months) subjects (HIV-1 RNA < 50 copies per mL) were randomised (1:1) and received either a rilpivirine plus cabotegravir regimen or remained on the CAR. Subjects randomised to receive the rilpivirine plus cabotegravir regimen initiated treatment with oral lead-in dosing with a cabotegravir (30 mg) tablet plus a rilpivirine (25 mg) tablet once daily for at least 4 weeks, followed by treatment with cabotegravir injection (month 1: 600 mg, month 2 onwards: 400 mg injection) plus rilpivirine injection (month 1: 900 mg injection, month 2 onwards: 600 mg injection), monthly, for an additional 44 weeks.
In ATLAS, 50%, 17%, and 33% of subjects received an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to randomisation and this was similar between treatment arms.

Pooled Phase 3 studies
At baseline, in the pooled analysis, in the rilpivirine plus cabotegravir arm the median age of subjects was 38 years, 27% were female, 27% were non-white, 1% were ≥ 65 years and 7% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment arms.

The primary endpoint of both studies was the proportion of subjects with plasma HIV-1 RNA ≥ 50 copies/mL at week 48 (snapshot algorithm for the ITT-E population).

In a pooled analysis of the two Phase 3 studies, rilpivirine plus cabotegravir was non-inferior to CAR on the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL (1.9% and 1.7% respectively) at week 48. The adjusted treatment difference between rilpivirine plus cabotegravir and CAR (0.2; 95% CI: -1.4, 1.7) met the non-inferiority criterion (upper bound of the 95% CI below 4%) [See Table 8].

The primary endpoint and other week 48 outcomes, including outcomes by key baseline factors, for FLAIR, ATLAS, and pooled data are shown in Table 8 and Table 9.

Table 8    Virologic outcomes of randomised treatment in FLAIR and ATLAS at week 48 (Snapshot analysis)
FLAIR                 ATLAS                  Pooled Data
RPV+ CAB CAR            RPV+ CAB CAR RPV+ CAB                  CAR
N=283        N=283      N=308       N=308    N=591         N=591
HIV-1                     6 (2.1)       7 (2.5)  5 (1.6)       3 (1.0) 11 (1.9)      10 (1.7) RNA ≥ 50 copies/mL†
Treatment Difference
% (95% CI)*                 -0.4 (-2.8, 2.1)       0.7 (-1.2, 2.5)         0.2 (-1.4, 1.7) HIV-1 RNA                         265 (93.6)        264            285 (92.5)       294        550           558 < 50 copies/mL                                     (93.3)                          (95.5)     (93.1)        (94.4) Treatment Difference                   0.4 (-3.7, 4.5)                -3.0 (-6.7, 0.7)          -1.4 (-4.1, 1.4) % (95% CI)*
No virologic data at               12 (4.2)         12 (4.2)        18 (5.8)     11 (3.6)    30 (5.1)       23 (3.9) week 48 window
Reasons
Discontinued study/study drug due to             8 (2.8)         2 (0.7)         11 (3.6)      5 (1.6)    19 (3.2)       7 (1.2) adverse event or death
Discontinued study/study drug for                4 (1.4)         10 (3.5)        7 (2.3)       6 (1.9)    11 (1.9)       16 (2.7) other reasons
Missing data during window but on study                    0               0               0             0           0             0 *   Adjusted for baseline stratification factors.
† Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.
N=Number of subjects in each treatment group, CI=confidence interval, CAR=current antiretroviral regimen, RPV=rilpivirine, CAB=cabotegravir.
Table 9      Proportion of subjects with plasma HIV-1 RNA ≥ 50 copies/mL at week 48 for key baseline factors (Snapshot outcomes)
Pooled data from FLAIR and ATLAS
Baseline factors                      RPV+CAB               CAR
N=591              N=591 n/N (%)            n/N (%)
Baseline CD4+                 < 350                           0/42            2/54 (3.7) (cells/ mm )
3                   ≥ 350 to < 500              5/120  (4.2)          0/117 ≥ 500                       6/429 (1.4)        8/420 (1.9)
Gender                        Male                        6/429 (1.4)        9/423 (2.1) Female                      5/162 (3.1)        1/168 (0.6)
Race                          White                       9/430 (2.1)        7/408 (1.7) Black African/American      2/109 (1.8)        3/133 (2.3)
Asian/Other                     0/52               0/48
BMI                           < 30 kg/m  2                6/491  (1.2)       8/488  (1.6) ≥ 30 kg/m  2                5/100 (5.0)        2/103 (1.9)
Age (years)                   < 50                        9/492 (1.8)        8/466 (1.7) ≥ 50                         2/99 (2.0)        2/125 (1.6)
Baseline antiviral            PI                           1/51 (2.0)            0/54 therapy at randomisation INI                              6/385 (1.6)        9/382 (2.4) NNRTI                       4/155 (2.6)        1/155 (0.6)
BMI=body mass index, PI=Protease inhibitor, INI=Integrase inhibitor, NNRTI=non-nucleoside reversetranscriptase inhibitor, RPV=rilpivirine, CAB=cabotegravir, CAR=current antiretroviral regimen 
In the FLAIR and ATLAS studies, treatment differences across baseline characteristics (CD4+ count, gender, age, race, BMI, baseline third agent treatment class) were comparable.

Week 96 FLAIR

In the FLAIR study at 96 Weeks, the results remained consistent with the results at 48 Weeks. The proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL in rilpivirine plus cabotegravir (n=283) and CAR (n=283) was 3.2% and 3.2% respectively (adjusted treatment difference between REKAMBYS plus cabotegravir and CAR [0.0; 95% CI: -2.9, 2.9]). The proportion of subjects having plasma HIV-1 RNA < 50 c/mL in REKAMBYS plus cabotegravir and CAR was 87% and 89%, respectively (adjusted treatment difference between REKAMBYS plus cabotegravir and CAR [-2.8; 95% CI: -8.2, 2.5]).

Week 124 FLAIR Direct to Injection versus Oral Lead-In

In the FLAIR study, an evaluation of safety and efficacy was performed at Week 124 for patients electing to switch at Week 100 from abacavir/dolutegravir/lamivudine to rilpivirine plus cabotegravir in the Extension Phase. Subjects were given the option to switch with and without an oral lead-in phase, creating an oral lead-in group and a direct to injection group.

At Week 124, the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL was 1/121 (0.8%) and 1/111 (0.9%) for the oral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1 RNA <50 c/mL) were similar in both the oral lead-in group (113/121 [93.4%]) and direct to injection group (110/111 [99.1%]).

Every 2 months dosing

Patients virologically suppressed (stable on prior ART for at least 6 months) The efficacy and safety of rilpivirine injection given every 2 months, has been evaluated in one Phase 3b randomised, multicentre, parallel-arm, open-label, non-inferiority study, ATLAS-2M (207966). The primary analysis was conducted after all subjects completed their week 48 visit or discontinued the study prematurely.

In ATLAS-2M, 1045 HIV-1 infected, ART-experienced, virologically suppressed subjects were randomised (1:1) and received a rilpivirine plus cabotegravir injection regimen administered either every 2 months or monthly. Subjects initially on non-cabotegravir/rilpivirine treatment received oral lead-in treatment comprising one rilpivirine tablet (25 mg) plus one cabotegravir tablet (30 mg), daily, for at least 4 weeks. Subjects randomised to monthly rilpivirine injections (month 1: 900 mg injection,month 2 onwards: 600 mg injection) and cabotegravir injections (month 1: 600 mg injection, month 2 onwards: 400 mg injection administered) received treatment for an additional 44 weeks. Subjects randomised to every 2 months rilpivirine injections (900 mg injection at months 1, 2, 4 and every 2 months thereafter) and cabotegravir injections (600 mg injection at months 1, 2, 4 and every 2 months thereafter) received treatment for an additional 44 weeks. Prior to randomisation, 63%, 13% and 24% of subjects received rilpivirine plus cabotegravir for 0 weeks, 1 to 24 weeks and > 24 weeks,respectively.

At baseline, the median age of subjects was 42 years, 27% were female, 27% were non-white, 4% were ≥65 years, and 6% had a CD4+ cell count less than 350 cells per mm3; these characteristics were similar between the treatment arms.

The primary endpoint in ATLAS-2M was the proportion of subjects with a plasma HIV-1 RNA ≥50 c/mL at week 48 (snapshot algorithm for the ITT-E population).

In ATLAS-2M, rilpivirine plus cabotegravir administered every 2 months was non-inferior to cabotegravir and rilpivirine administered every month on the proportion of subjects having plasma HIV-1 RNA ≥ 50 c/mL (1.7% and 1.0% respectively) at week 48. The adjusted treatment difference between cabotegravir plus rilpivirine administered every 2 months and every month (0.8; 95% CI: - 0.6, 2.2) met the non-inferiority criterion (upper bound of the 95% CI below 4%).

Table 10    Virologic outcomes of randomised treatment of ATLAS-2M at 48 weeks (Snapshot analysis)
Every 2 months              Monthly Dosing (Q4W)
Dosing
(Q8W)
N=522 (%)                     N=523 (%)
HIV-1 RNA≥ 50 copies/mL†                         9                        5 (1.0) (1.7)
Treatment Difference % (95%
0.8 (-0.6,
CI)*
2.2)
HIV-1 RNA < 50 copies/mL                  492 (94.3)                    489 (93.5) Treatment Difference % (95%
0.8 (-2.1,
CI)*
3.7)
No virologic data at week 48                    21                        29 (5.5) window                                         (4.0)
Reasons:
Discontinued study due to AEor                9                        13 (2.5) death                                      (1.7)
Discontinued study for other                 12                        16 (3.1) reasons                                     (2.3)
On study but missing data in                  0                           0 window
* Adjusted for baseline stratification factors.
† Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.
N=Number of subjects in each treatment group, CI=confidence interval, CAR=current antiretroviral regimen.

Table 11      Proportion of subjects with plasma HIV-1 RNA ≥ 50 copies/mL in ATLAS-2M at week 48 for key baseline factors (Snapshot outcomes).
Number of HIV-1 RNA ≥ 50 c/mL/ Total Assessed (%)
Baseline factors               Every 2 months dosing
Monthly dosing (Q4W)
(Q8W)
< 350                   1/ 35 (2.9)             1/ 27 (3.7)
Baseline CD4+ cell         350 to < 500              1/ 96 (1.0)                   0/ 89 count (cells/mm3)          ≥ 500                     7/391 (1.8)                4/407 (1.0) Gender                     Male                      4/385 (1.0)                5/380 (1.3) Female                    5/137 (3.5)                   0/143
Race                       White                     5/370 (1.4)                5/393 (1.3) Non-White                 4/152 (2.6)                   0/130
Black/African
4/101 (4.0)                   0/ 90
American
Non-
Black/African             5/421 (1.2)                5/421 (1.2)
American
BMI                        < 30 kg/m2                3/409 (0.7)                3/425 (0.7) ≥ 30 kg/m2                6/113 (5.3)                 2/98 (2.0)
Age (years)                < 35                      4/137 (2.9)                1/145 (0.7) 35 to < 50                3/242 (1.2)                2/239 (0.8)
≥ 50                      2/143 (1.4)                2/139 (1.4)
Prior exposure             None                      5/327 (1.5)                5/327 (1.5) CAB/RPV                    1-24 weeks                 3/69 (4.3)                    0/68 > 24 weeks                1/126 (0.8)                   0/128
BMI=body mass index, CAB=cabotegravir, RPV=rilpivirine

In the ATLAS-2M study, treatment differences on the primary endpoint across baseline characteristics (CD4+ lymphocyte count, gender, race, BMI, age and prior exposure to cabotegravir/rilpivirine) were not clinically meaningful.

The efficacy results at Week 96 are consistent with the results of the primary endpoint at Week 48.
Rilpivirine plus cabotegravir injections administered every 2 months is non-inferior to rilpivirine and cabotegravir administered every month. The proportion of subjects having plasma HIV-1 RNA ≥50 c/mL at Week 96 in rilpivirine plus cabotegravir every 2 months dosing (n=522) and rilpivirine plus cabotegravir monthly dosing (n=523) was 2.1% and 1.1% respectively (adjusted treatment difference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing [1.0; 95% CI: -0.6, 2.5]). The proportion of subjects having plasma HIV-1 RNA <50 c/mL at Week 96 in rilpivirine plus cabotegravir every 2 months dosing and rilpivirine plus cabotegravir monthly dosing was 91% and 90.2% respectively (adjusted treatment difference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing [0.8; 95% CI: -2.8, 4.3]).

The efficacy results at Week 152 are consistent with the results of the primary endpoint at Week 48 and at Week 96. Rilpivirine plus cabotegravir injections administered every 2 months is non-inferior to rilpivirine and cabotegravir administered every month. In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA ≥50 c/mL at Week 152 in rilpivirine plus cabotegravir every 2 months dosing (n=522) and rilpivirine plus cabotegravir monthly dosing (n=523) was 2.7% and 1.0% respectively (adjusted treatment difference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing [1.7; 95% CI: 0.1, 3.3]). In an ITT analysis, the proportion of subjects having plasma HIV-1 RNA <50 c/mL at Week 152 in rilpivirine plus cabotegravir every 2 months dosing and rilpivirine plus cabotegravir monthly dosing was 87% and 86% respectively (adjusted treatment difference between rilpivirine plus cabotegravir every 2 months dosing and monthly dosing [1.5; 95% CI: -2.6, 5.6]).

Post-hoc analyses
Multivariable analyses of pooled Phase 3 studies (ATLAS through 96 weeks, FLAIR through 124 weeks, ATLAS-2M through 152 weeks) examined the influence of various factors on the risk of CVF. The baseline factors analysis (BFA) examined baseline viral and participants characteristics and dosing regimen; and the multivariable analysis (MVA) included the baseline factors and incorporated post-baseline predicted plasma drug concentrations on CVF using regression modelling with a variable selection procedure. Following a total of 4291 person-years, the unadjusted CVF incidence rate was 0.54 per 100 person-years; 23 CVFs were reported (1.4% of 1651 individuals in these studies).

The BFA demonstrated rilpivirine resistance mutations (incidence rate ratio IRR=21.65, p<0.0001), HIV-1 subtype A6/A1 (IRR=12.87, p<0.0001), and body mass index IRR=1.09 per 1 unit increase, p=0.04; IRR=3.97 of ≥30 kg/m2, p=0.01) were associated with CVF. Other variables including Q4W or Q8W dosing, female gender, or CAB/INSTI resistance mutations had no significant association with CVF. A combinationof at least 2 of the following key baseline factors was associated with an increased risk of CVF: rilpivirine resistance associated mutations, HIV-1 subtype A6/A1, or BMI ≥ 30 kg/m2 (Table 12).

Table 12          Week 48 Outcomes by Presence of Key Baseline Factors of rilpivirine resistance associated mutations, HIV-1 Subtype A6/A11 and BMI ≥ 30 kg/m2
Confirmed Virologic
Baseline Factors (number)         Virologic Successes2
Failure (%)3
0                       844/970 (87.0)                4/970 (0.4)
1                       343/404 (84.9)                8/404 (2.0)4
≥2                        44/57 (77.2)                  11/57 (19.3)5 TOTAL                     1231/1431 (86/0)               23/1431 (1.6)6 (95% Confidence Interval)           (84.1%, 87.8%)                 (1.0%, 2.4%) 1    HIV-1 subtype A1 or A6 classification based on Los Alamos National Library panel from HIV Sequence database (June 2020)
2    Based on the FDA Snapshot algorithm of RNA <50 copies/mL at Week 48 for ATLAS, at Week 124 for FLAIR, at
Week 152 for ATLAS-2M.
3    Defined as two consecutive measurements of HIV RNA ≥ 200 copies/mL.
4    Positive Predictive Value (PPV) <1%; Negative Predictive Value (NPV) 98.5%; sensitivity 34.8%; specificity 71.9%
5    PPV 19.3%; NPV 99.1%; sensitivity 47.8%; specificity 96.7%
6    Analysis dataset with all non-missing covariates for baseline factors (out of a total of 1651 individuals).

In patients with at least two of these risk factors, the proportion of subjects who had a CVF was higher than observed in patients with none or one risk factor, with CVF identified in 6/24 patients [25.0%, 95% CI (9.8%, 46.7%)] treated with the every 2 months dosing regimen and 5/33 patients [15.2%, 95% CI (5.1%, 31.9%)] treated with the monthly dosing regimen.

Pharmacokinetic Properties

5.2        Pharmacokinetic properties

The pharmacokinetic properties of REKAMBYS have been evaluated in healthy and HIV-1 infected adults.

Table 13 Population pharmacokinetic parameters following once-daily oral rilpivirine and following initiation and monthly or every two months continuation intramuscular injections of REKAMBYS
Geometric mean (5th; 95th Percentile)
Dosing phase       Dose regimen        AUC(0-tau)b          Cmax                Ctaub (ng•h/mL)          (ng/mL)             (ng/mL)
 c           25 mg                   2,083                  116                     79.4 Oral Lead-In             once daily            (1,125; 3,748)           (48.6; 244)             (31.8; 177) a,d      900 mg IM                  44,842                   144                     41.9 Initial Injection            initial dose         (21,712; 87,575)           (93.9; 221)             (21.7; 78.9) Monthlya,e              600 mg IM                  68,324                   121                     85.8 Injection                  monthly            (39,042; 118,111)          (68.1; 210)             (49.6; 147) Every 2 months a,e
900 mg IM                 132,450                   138                     68.9 Injection              every 2 months         (76,638; 221,783)          (80.6; 228)             (38.0; 119) a.   Based on individual post-hoc estimates from rilpivirine IM population pharmacokinetic model (pooled data FLAIR, ATLAS and ATLAS-2M).
b.   tau is dosing interval: 24 hours for oral; 1 or 2 months for monthly or every 2 months IM injections.
c.   For oral rilpivirine, Ctau represents observed pooled data FLAIR, ATLAS and ATLAS-2M, AUC(0-tau) and Cmax represent pharmacokinetic data from oral rilpivirine Phase 3 studies d.   When administered with oral lead-in, initial injection Cmax primarily reflects oral dosing because the initial injection was administered on the same day as the last oral dose. When administered without oral lead-in (direct to injection, n=110), the rilpivirine observed geometric mean (5th, 95th percentile) Cmax (1 week post initial injection) was 68.0 ng/mL (27.5, 220) and the Ctau was 48.9 ng/mL (17.7, 138).
e.   Week 48 data.


Absorption
Rilpivirine prolonged-release injection exhibits absorption rate-limited kinetics (i.e., flip-flop pharmacokinetics) resulting from slow absorption from the gluteal muscle into the systemic circulation resulting in sustained rilpivirine plasma concentrations.

Following a single intramuscular dose, rilpivirine plasma concentrations are detectable the first day and gradually rise to reach maximum plasma concentrations after a median of 3-4 days. Rilpivirine has been detected in plasma up to 52 weeks or longer after administration of a single dose of REKAMBYS. After 1 year of monthly or every 2 months injections, approximately 80% of the rilpivirine pharmacokinetic steady-state exposure is reached.

Plasma rilpivirine exposure increases in proportion or slightly less than in proportion to dose following single and repeat IM injections of doses ranging from 300 to 1200 mg.

Distribution

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. Based on population pharmacokinetics analysis, the typical apparent volume of the central compartment (Vc/F) for rilpivirine after IM administration was estimated to be 132 L, reflecting a moderate distribution to peripheral tissues.

Rilpivirine is present in cerebrospinal fluid (CSF). In HIV-1-infected subjects receiving a regimen of rilpivirine injection plus cabotegravir injection, the median rilpivirine CSF to plasma concentration ratio (n=16) was 1.07 to 1.32% (range: not quantifiable to 1.69%). Consistent with therapeutic rilpivirine concentrations in the CSF, CSF HIV-1 RNA (n=16) was < 50 c/mL in 100% and < 2 c/mL in 15/16 (94%) of subjects. At the same time point, plasma HIV-1 RNA (n=18) was < 50 c/mL in 100% and < 2 c/mL in 12/18 (66.7%) of subjects.

Biotransformation

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.

Elimination

The mean apparent half-life of rilpivirine following REKAMBYS administration is absorption rate-limited and was estimated to be 13-28 weeks.

The apparent plasma clearance (CL/F) of rilpivirine was estimated to be 5.08 L/h.

After single dose administration of oral 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.

Special patient populations

Gender
No clinically relevant differences in the rilpivirine exposure after intramuscular (IM) administration have been observed between men and women.

Race
No clinically relevant effect of race on the rilpivirine exposure after intramuscular administration has been observed.

BMI
No clinically relevant effect of BMI on the rilpivirine exposure after intramuscular administration has been observed.

Elderly
No clinically relevant effect of age on the rilpivirine exposure after intramuscular administration has been observed. Pharmacokinetic data for rilpivirine in subjects of > 65 years old are limited.

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, REKAMBYS 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 REKAMBYS 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).

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 oral 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.
REKAMBYS has not been studied in patients with severe hepatic impairment (Child-Pugh score C).
Therefore, REKAMBYS is not recommended in patients with severe hepatic impairment (see section 4.2).

HBV/HCV Co-infected Patients
Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the rilpivirine exposure after oral rilpivirine intake.

Paediatric Patients
The phamacokinetics of rilpivirine in children and adolescents aged < 18 years have not been established with REKAMBYS.