Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR17.



Mechanism of action

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of 2’-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral deoxyribonucleic acid (DNA) by the HIV reverse transcriptase (RT), which results in DNA chain- termination. Emtricitabine has activity against HIV-1, HIV-2, and HBV.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analogue). Tenofovir alafenamide is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil fumarate in concentrating tenofovir in peripheral blood mononuclear cells (PBMCs) or HIV target cells including lymphocytes and macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV RT, which results in DNA chain- termination.

Tenofovir has activity against HIV-1, HIV-2, and HBV.

Antiviral activity in vitro
Emtricitabine and tenofovir alafenamide demonstrated synergistic antiviral activity in cell culture. No antagonism was observed with emtricitabine or tenofovir alafenamide when combined with other antiretroviral agents.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013 to 0.64 μM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 μM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4+-T lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to 14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups (M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

Resistance

In vitro
Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.
HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed.

In treatment-naïve patients
In a pooled analysis of antiretroviral-naïve patients receiving emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet in Phase 3 studies GS-US-292-0104 and GS-US-292-0111, genotyping was performed on plasma HIV-1 isolates from all patients with HIV-1 RNA ≥ 400 copies/mL at confirmed virological failure, at Week 144, or at the time of early study drug discontinuation. Through Week 144, the development of one or more primary emtricitabine, tenofovir alafenamide, or elvitegravir resistance-associated mutations was observed in HIV-1 isolates from 12 of 22 patients with evaluable genotypic data from paired baseline and E/C/F/TAF treatment-failure isolates (12 of 866 patients [1.4%]) compared with 12 of 
20 treatment-failure isolates from patients with evaluable genotypic data in the E/C/F/TDF group (12 of 867 patients [1.4%]). In the E/C/F/TAF group, the mutations that emerged were M184V/I (n = 11) and K65R/N (n = 2) in RT and T66T/A/I/V (n = 2), E92Q (n = 4), Q148Q/R (n = 1), and N155H (n = 2) in integrase. Of the HIV-1 isolates from 12 patients with resistance development in the E/C/F/TDF group, the mutations that emerged were M184V/I (n = 9), K65R/N (n = 4), and L210W (n=1) in RT and E92Q/V (n = 4) and Q148R (n = 2) and N155H/S (n=3) in integrase. Most HIV-1 isolates from patients in both treatment groups who developed resistance mutations to elvitegravir in integrase also developed resistance mutations to emtricitabine in RT.

In patients co-infected with HIV and HBV
In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, who received emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF), for 48 weeks (GS-US-292-1249, n = 72), 2 patients qualified for resistance analysis. In these 2 patients, no amino acid substitutions associated with resistance to any of the components of E/C/F/TAF were identified in HIV-1 or HBV.

Cross-resistance in HIV-1 infected, treatment-naïve or virologically suppressed patients Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Multinucleoside-resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to tenofovir alafenamide.

Clinical data

There are no efficacy and safety studies conducted in treatment-naïve patients with Descovy.
Clinical efficacy of Descovy was established from studies conducted with emtricitabine and tenofovir alafenamide when given with elvitegravir and cobicistat as the fixed-dose combination tablet E/C/F/TAF.

HIV-1 infected, treatment-naïve patients
In studies GS-US-292-0104 and GS-US-292-0111, patients were randomised in a 1:1 ratio to receive either emtricitabine 200 mg and tenofovir alafenamide 10 mg (n = 866) once daily or emtricitabine 200 mg + tenofovir disoproxil (as fumarate) 245 mg (n = 867) once daily, both given with elvitegravir
150 mg + cobicistat 150 mg as a fixed-dose combination tablet. The mean age was 36 years (range: 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of patients were identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL (range: 1.3-7.0) and 23% had baseline viral loads > 100,000 copies/mL. The mean baseline CD4+ cell count was 427 cells/mm3 (range: 0-1,360) and 13% had a CD4+ cell count < 200 cells/mm3.

E/C/F/TAF demonstrated statistical superiority in achieving HIV-1 RNA < 50 copies/mL when compared to E/C/F/TDF at Week 144. The difference in percentage was 4.2% (95% CI: 0.6% to 7.8%). Pooled treatment outcomes at 48 and 144 weeks are shown in Table 4.



Table 4: Pooled virological outcomes of Studies GS-US-292-0104 and GS-US-292-0111 at Weeks 48 and 144a,b
Week 48                                       Week 144
E/C/F/TAF         E/C/F/TDFe                  E/C/F/TAF         E/C/F/TDF (n = 866)         (n = 867)                   (n = 866)          (n = 867) HIV-1 RNA < 50 copies/mL                  92%               90%                        84%                80% Treatment difference               2.0% (95% CI: -0.7% to 4.7%)                  4.2% (95% CI: 0.6% to 7.8%) HIV-1 RNA ≥ 50 copies/mLc                 4%                 4%                         5%                 4% No virologic data at                      4%                 6%                        11%                16% Week 48 or 144 window
Discontinued study drug                1%                     2%                     1%                     3% due to AE or deathd
Discontinued study drug                2%                     4%                     9%                     11% due to other reasons and last available
HIV-1 RNA
< 50 copies/mLe
Missing data during                    1%                    < 1%                    1%                     1% window but on study drug
Proportion (%) of patients with HIV-1 RNA
< 50 copies/mL by subgroup
Age
< 50 years                      716/777 (92%)          680/753 (90%)          647/777 (83%)           602/753 (80%) ≥ 50 years                       84/89 (94%)           104/114 (91%)           82/89 (92%)            92/114 (81%) 
Sex
Male                          674/733 (92%)          673/740 (91%)          616/733 (84%)           603/740 (81%) Female                        126/133 (95%)          111/127 (87%)          113/133 (85%)           91/127 (72%) 
Race
Black                            197/223 (88%)          177/213 (83%)          168/223 (75%)           152/213 (71%) Non-black                        603/643 (94%)          607/654 (93%)          561/643 (87%)           542/654 (83%) 
Baseline viral load
≤ 100,000 copies/mL             629/670 (94%)          610/672 (91%)          567/670 (85%)           537/672 (80%) > 100,000 copies/mL             171/196 (87%)          174/195 (89%)          162/196 (83%)           157/195 (81%) 
Baseline CD4+ cell count
< 200 cells/mm3                  96/112 (86%)          104/117 (89%)          93/112 (83%)            94/117 (80%) ≥ 200 cells/mm3                 703/753 (93%)          680/750 (91%)          635/753 (84%)           600/750 (80%) 
HIV-1 RNA < 20 copies/mL                 84.4%                  84.0%                  81.1%                   75.8% Treatment difference          0.4% (95% CI: -3.0% to 3.8%)                   5.4% (95% CI: 1.5% to 9.2%) 
E/C/F/TAF = elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate a Week 48 window was between Day 294 and 377 (inclusive): Week 144 window was between Day 966 and 1049 (inclusive).
b In both studies, patients were stratified by baseline HIV-1 RNA (≤ 100,000 copies/mL, > 100,000 copies/mL to ≤ 400,000 copies/mL, or > 400,000 copies/mL), by CD4+ cell count (< 50 cells/μL, 50-199 cells/μL, or ≥ 200 cells/μL), and by region (US or ex-US).
c Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
d Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

The mean increase from baseline in CD4+ cell count was 230 cells/mm3 in patients receiving E/C/F/TAF and 211 cells/mm3 in patients receiving E/C/F/TDF(p = 0.024) at Week 48, and 326 cells/mm3 in E/C/F/TAF-treated patients and 305 cells/mm3 in E/C/F/TDF-treated patients (p = 0.06) at Week 144.

Clinical efficacy of Descovy in treatment-naïve patients was also established from a study conducted with emtricitabine and tenofovir alafenamide (10 mg) when given with darunavir (800 mg) and cobicistat as a fixed-dose combination tablet (D/C/F/TAF). In Study GS-US-299-0102, patients were randomised in a 2:1 ratio to receive either fixed-dose combination D/C/F/TAF once daily (n = 103) or darunavir and cobicistat and emtricitabine/tenofovir disoproxil fumarate once daily (n = 50). The proportions of patients with plasma HIV-1 RNA < 50 copies/mL and < 20 copies/mL are shown in Table 5.

Table 5: Virological outcomes of Study GS-US-299-0102 at Week 24 and 48a 
Week 24                                          Week 48
D/C/F/TAF             Darunavir,                 D/C/F/TAF             Darunavir, (n = 103)          cobicistat and                (n = 103)          cobicistat and emtricitabine/tenofovir                          emtricitabine/tenofovir disoproxil fumarate                              disoproxil fumarate
(n = 50)                                         (n = 50)
HIV-1 RNA                           75%                   74%                        77%                   84% < 50 copies/mL
Treatment difference          3.3% (95% CI: -11.4% to 18.1%)                   -6.2% (95% CI: -19.9% to 7.4%) HIV-1 RNA                           20%                24%                           16%                 12% ≥ 50 copies/mLb
No virologic data at                 5%                        2%                     8%                      4% Week 48 window
Discontinued study               1%                        0                      1%                      2% drug due to AE or deathc
Discontinued study drug due to other reasons and last                 4%                        2%                     7%                      2% available HIV-1 RNA
< 50 copies/mLd
Missing data during               0                        0                       0                        0 window but on study drug
HIV-1 RNA                           55%                      62%                     63%                      76% < 20 copies/mL
Treatment difference           -3.5% (95% CI: -19.8% to 12.7%)                  -10.7% (95% CI: -26.3% to 4.8%) D/C/F/TAF = darunavir/cobicistat/emtricitabine/tenofovir alafenamide a Week 48 window was between Day 294 and 377 (inclusive).
b Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
c Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
d Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

HIV-1 infected virologically suppressed patients
In Study GS-US-311-1089, the efficacy and safety of switching from emtricitabine/tenofovir disoproxil fumarate to Descovy while maintaining the third antiretroviral agent were evaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults (n = 663). Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months and had HIV-1 with no resistance mutations to emtricitabine or tenofovir alafenamide prior to study entry. Patients were randomised in a 1:1 ratio to either switch to Descovy (n = 333), or stay on their baseline emtricitabine/tenofovir disoproxil fumarate containing regimen (n = 330). Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 46% of patients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with a boosted PI 

and 54% of patients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with an unboosted third agent.

Treatment outcomes of Study GS-US-311-1089 through 48 and 96 weeks are presented in Table 6.

Table 6: Virological outcomes of Study GS-US-311-1089 at Weeks 48a and 96b 
Week 48                                Week 96
Descovy containing Emtricitabine/tenof Descovy containing Emtricitabine/tenof regimen         ovir disoproxil        regimen          ovir disoproxil (n = 333)      fumarate containing     (n = 333)      fumarate containing regimen                                 regimen
(n = 330)                         (n = 330)
HIV-1 RNA                          94%                93%                 89%                 89% < 50 copies/mL
Treatment difference               1.3% (95% CI: -2.5% to 5.1%)                     -0.5% (95% CI: -5.3% to 4.4%) HIV-1 RNA                            < 1%                 2%                           2%                  1% ≥ 50 copies/mLc
No virologic data at                  5%                        5%                     9%                      10% Week 48 or 96 window
Discontinued study                2%                        1%                     2%                       2% drug due to AE or deathd
Discontinued study                                                                 7%                       9% drug due to other reasons and last
3%                        5% available
HIV-1 RNA
< 50 copies/mLe
Missing data during              < 1%                       0                       0                      <1% window but on study drug
Proportion (%) of patients with
HIV-1 RNA
< 50 copies/mL by prior treatment regimen
Boosted PIs                 142/155 (92%)           140/151 (93%)            133/155 (86%)           133/151 (88%) Other third agents          172/178 (97%)           167/179 (93%)            162/178 (91%)           161/179 (90%) PI = protease inhibitor a Week 48 window was between Day 294 and 377 (inclusive).
b Week 96 window was between Day 630 and 713 (inclusive).
c Includes patients who had ≥ 50 copies/mL in the Week 48 or Week 96 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
d Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.


In Study GS-US-311-1717, patients who were virologically suppressed (HIV-1 RNA <50 copies/mL) on their abacavir/lamivudine containing regimen for at least 6 months were randomised in a 1:1 ratio to either switch to Descovy (N=280) while maintaining their third agent at baseline or stay on their baseline abacavir/lamivudine -containing regimen (N=276).

Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 30% of patients were receiving abacavir/lamivudine in combination with a boosted protease inhibitor and 70% of patients were receiving abacavir/lamivudine in combination with an unboosted third agent.
Virologic success rates at Week 48 were: Descovy Containing Regimen: 89.7% (227 of 253 subjects); Abacavir/lamivudine Containing Regimen: 92.7%% (230 of 248 subjects). At Week 48, switching to a Descovy-containing regimen was non-inferior to staying on a baseline abacavir/lamivudine-containing regimen in maintaining HIV-1 RNA < 50 copies/mL

HIV-1 infected patients with mild to moderate renal impairment
In Study GS-US-292-0112, the efficacy and safety of emtricitabine and tenofovir alafenamide were evaluated in an open-label clinical study in which 242 HIV-1 infected patients with mild to moderate renal impairment (eGFRCG: 30-69 mL/min) were switched to emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.

The mean age was 58 years (range: 24-82), with 63 patients (26%) who were ≥ 65 years of age.
Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of patients were identified as Hispanic/Latino. At baseline, median eGFR was 56 mL/min, and 33% of patients had an eGFR from 30 to 49 mL/min. The mean baseline CD4+ cell count was 664 cells/mm3 (range: 126-1,813).

At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching to emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet

In Study GS-US-292-1825, the efficacy and safety of emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet were evaluated in a single arm, open-label clinical study in which 55 HIV-1 infected adults with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis for at least 6 months before switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.

The mean age was 48 years (range 23-64). Seventy-six percent were male, 82% were Black and 18% were White. Fifteen percent of patients identified as Hispanic/Latino. The mean baseline CD4+ cell count was 545 cells/mm3 (range 205-1473). At Week 48, 81.8% (45/55 patients) maintained HIV-1 RNA < 50 copies/mL after switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. There were no clinically significant changes in fasting lipid laboratory tests in patients who switched.

Patients co-infected with HIV and HBV
In open-label Study GS-US-292-1249, the efficacy and safety of emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF), were evaluated in adult patients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the 72 patients were on prior TDF-containing antiretroviral therapy. At the start of treatment with E/C/F/TAF, the 72 patients had been HIV-suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months with or without suppression of HBV DNA and had compensated liver function. The mean age was 50 years (range 28-67), 92% of patients were male, 69% were White, 18% were Black, and 10% were Asian. The mean baseline CD4+ cell count was 636 cells/mm3 (range 263-1498).
Eighty-six percent of patients (62/72) were HBV suppressed (HBV DNA < 29 IU/mL) and 42% (30/72) were HBeAg positive at baseline.

Of the patients who were HBeAg positive at baseline, 1/30 (3.3%) achieved seroconversion to anti-HBe at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achieved seroconversion to anti-HBs Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. The mean change from baseline in CD4+ cell count at Week 48 was -2 cells/mm3.
Ninety-two percent (66/72 patients) had HBV DNA < 29 IU/mL using missing = failure analysis at Week 48. Of the 62 patients who were HBV suppressed at baseline, 59 remained suppressed and 

3 had missing data. Of the 10 patients who were not HBV suppressed at baseline (HBV DNA ≥ 29 IU/mL), 7 became suppressed, 2 remained detectable, and 1 had missing data.

There are limited clinical data on the use of E/C/F/TAF in HIV/HBV co-infected patients who are treatment-naïve.

Changes in measures of bone mineral density
In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet was associated with smaller reductions in bone mineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dual energy X ray absorptiometry (DXA) analysis of hip (mean change:-0.8% vs -3.4%, p < 0.001) and lumbar spine (mean change:-0.9% vs -3.0%, p < 0.001). In a separate study, emtricitabine and tenofovir alafenamide given with darunavir and cobicistat as a fixed-dose combination tablet was also associated with smaller reductions in BMD (as measured by hip and lumbar spine DXA analysis) through 48 weeks of treatment compared to darunavir, cobicistat, emtricitabine and tenofovir disoproxil fumarate.

In a study in virologically suppressed adult patients, improvements in BMD were noted through 96 weeks after switching to Descovy from a TDF containing regimen compared to minimal changes with maintaining the TDF containing regimen as measured by DXA analysis of hip (mean change from baseline of 1.9% vs -0.3%, p < 0.001) and lumbar spine (mean change from baseline of 2.2% vs -0.2%, p < 0.001).

In a study in virologically suppressed adult patients, BMD did not change significantly through 48 weeks after switching to Descovy from an abacavir/lamivudine containing regimen compared to maintaining the abacavir/lamivudine containing regimen as measured by DXA analysis of hip (mean change from baseline of 0.3% vs 0.2%, p = 0.55) and lumbar spine (mean change from baseline of 0.1% vs < 0.1%, p = 0.78).

Changes in measures of renal function
In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet through 144 weeks was associated with a lower impact on renal safety parameters (as measured after 144 weeks treatment by eGFRCG and urine protein to creatinine ratio and after 96 weeks treatment by urine albumin to creatinine ratio) compared to E/C/F/TDF. Through 144 weeks of treatment, no subject discontinued E/C/F/TAF due to a treatment-emergent renal adverse event compared with 12 subjects who discontinued E/C/F/TDF (p < 0.001).

In a separate study in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with darunavir and cobicistat as a fixed-dose combination tablet was associated with a lower impact on renal safety parameters through 48 weeks of treatment compared to darunavir and cobicistat given with emtricitabine/tenofovir disoproxil fumarate (see also section 4.4).

In a study in virologically suppressed adult patients measures of tubular proteinuria were similar in patients switching to a regimen containing Descovy compared to patients who stayed on an abacavir/lamivudine containing regimen at baseline. At Week 48, the median percentage change in urine retinol binding protein to creatinine ratio was 4% in the Descovy group and 16% in those remaining on an abacavir/lamivudine containing regimen; and in urine beta-2 microglobulin to creatinine ratio it was 4% vs. 5%.


Paediatric population
In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine and tenofovir alafenamide were evaluated in an open-label study in which 50 HIV-1 infected, treatment-naïve adolescents received emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a mean age of 15 years (range: 12-17), and 
56% were female, 12% were Asian, and 88% were Black. At baseline, median plasma HIV-1 RNA was 4.7 log10 copies/mL, median CD4+ cell count was 456 cells/mm3 (range: 95-1,110), and median CD4+% was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 RNA > 100,000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar to response rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at Week 48 was 224 cells/mm3. No emergent resistance to E/C/F/TAF was detected through Week 48.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the (mean ± SD) steady state plasma emtricitabine peak concentrations (Cmax) were 1.8 ± 0.7 μg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 μg•h/mL. The mean steady state plasma trough concentration at 24 hours post-dose was equal to or greater than the mean in vitro IC90 value for anti-HIV-1 activity.

Emtricitabine systemic exposure was unaffected when emtricitabine was administered with food.

Following administration of food in healthy subjects, peak plasma concentrations were observed approximately 1 hour post-dose for tenofovir alafenamide administered as F/TAF (25 mg) or E/C/F/TAF (10 mg). The mean Cmax and AUClast, (mean ± SD) under fed conditions following a single 25 mg dose of tenofovir alafenamide administered in Descovy were 0.21 ± 0.13 μg/mL and 0.25 ± 0.11 μg•h/mL, respectively. The mean Cmax and AUClast following a single 10 mg dose of tenofovir alafenamide administered in E/C/F/TAF were 0.21 ± 0.10 μg/mL and 0.25 ± 0.08 μg•h/mL, respectively.

Relative to fasting conditions, the administration of tenofovir alafenamide with a high fat meal (~800 kcal, 50% fat) resulted in a decrease in tenofovir alafenamide Cmax (15-37%) and an increase in AUClast (17-77%).

Distribution

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02-200 μg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.

In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration over the range of 0.01-25 μg/mL. Ex vivo binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies was approximately 80%.

Biotransformation

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. Following administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~86%) and faeces (~14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (~4% of dose). No other metabolites were identifiable.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target 
cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite tenofovir diphosphate. In human clinical studies, a 10 mg oral dose of tenofovir alafenamide (given with emtricitabine and elvitegravir and cobicistat) resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of tenofovir disoproxil (as fumarate) (given with emtricitabine and elvitegravir and cobicistat).

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administration with the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not significantly affected. Following administration of tenofovir alafenamide, plasma [14C]-radioactivity showed a time-dependent profile with tenofovir alafenamide as the most abundant species in the initial few hours and uric acid in the remaining period.

Elimination

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.
Tenofovir is renally eliminated by both glomerular filtration and active tubular secretion.

Pharmacokinetics in special populations

Age, gender, and ethnicity
No clinically relevant pharmacokinetic differences due to age, gender or ethnicity have been identified for emtricitabine, or tenofovir alafenamide.

Paediatric population

Exposures of emtricitabine and tenofovir alafenamide (given with elvitegravir and cobicistat) achieved in 24 paediatric patients aged 12 to < 18 years who received emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat in Study GS-US-292-0106 were similar to exposures achieved in treatment-naïve adults (Table 7).



Table 7: Pharmacokinetics of emtricitabine and tenofovir alafenamide in antiretroviral-naïve adolescents and adults

Adolescents                                  Adults a
FTC            TAFb          TFV  b
FTC a
TAFc           TFVc
AUCtau            14,424.4        242.8         275.8         11,714.1       206.4          292.6 (ng•h/mL)          (23.9)         (57.8)        (18.4)          (16.6)       (71.8)         (27.4) Cmax              2,265.0         121.7       14.6 (20.0)      2,056.3       162.2           15.2 (ng/mL)            (22.5)         (46.2)                        (20.2)       (51.1)         (26.1) Ctau                                          10.0 (19.6)                                    10.6 102.4 (38.9)b       N/A                      95.2 (46.7)        N/A
(ng/mL)                                                                                     (28.5) E/C/F/TAF = elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir N/A = not applicable
Data are presented as mean (%CV).
a n = 24 adolescents (GS-US-292-0106); n = 19 adults (GS-US-292-0102) b n = 23 adolescents, (GS-US-292-0106, population PK analysis) c n = 539 (TAF) or 841 (TFV) adults (GS-US-292-0111 and GS-US-292-0104, population PK analysis) 
Renal impairment
No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (estimated CrCl ≥ 15 mL/min and < 30 mL/min) in a Phase 1 study of tenofovir alafenamide. In a separate Phase 1 study of emtricitabine alone, mean systemic emtricitabine exposure was higher in patients with severe renal impairment (estimated CrCl < 30 mL/min) (33.7 μg•h/mL) than in subjects with normal renal function (11.8 μg•h/mL). The safety of emtricitabine and tenofovir alafenamide has not been established in patients with severe renal impairment (estimated CrCl ≥ 15 mL/min and < 30 mL/min).

Exposures of emtricitabine and tenofovir in 12 patients with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis who received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in Study GS-US-292-1825 were significantly higher than in patients with normal renal function. No clinically relevant differences in tenofovir alafenamide pharmacokinetics were observed in patients with end stage renal disease on chronic haemodialysis as compared to those with normal renal function.
There were no new safety issues identified in patients with end stage renal disease on chronic haemodialysis receiving emtricitabine and tenofovir alafenamide, in combination with elvitegravir and cobicistat as a fixed-dose combination tablet (see section 4.8).

There are no pharmacokinetic data on emtricitabine or tenofovir alafenamide in patients with end stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis. The safety of emtricitabine and tenofovir alafenamide has not been established in these patients.

Hepatic impairment
The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.

Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than those seen in subjects with normal hepatic function. When corrected for protein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment and normal hepatic function are similar.

Hepatitis B and/or hepatitis C virus co-infection
The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in patients co-infected with HBV and/or HCV.