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Pharmacology: Pharmacodynamics: 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 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 emtricitabine and tenofovir alafenamide fumarate.
Clinical efficacy of emtricitabine and tenofovir alafenamide fumarate 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 randomized 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 1. (See Table 1.)
Click on icon to see table/diagram/imageThe 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 emtricitabine and tenofovir alafenamide fumarate 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 randomized 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 2. (See Table 2)
Click on icon to see table/diagram/imageHIV-1 infected virologically suppressed patients: In study GS-US-311-1089, the efficacy and safety of switching from emtricitabine/tenofovir disoproxil fumarate to emtricitabine and tenofovir alafenamide fumarate while maintaining the third antiretroviral agent were evaluated in a randomized, 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 randomized in a 1:1 ratio to either switch to emtricitabine and tenofovir alafenamide fumarate (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 3. (See Table 3.)
Click on icon to see table/diagram/imageIn 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 Emtricitabine + tenofovir alafenamide (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: Emtricitabine + tenofovir alafenamide Containing Regimen: 89.7% (227 of 253 subjects); Abacavir/lamivudine Containing Regimen: 92.7% (230 of 248 subjects). At Week 48, switching to a Emtricitabine and tenofovir alafenamide-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 emtricitabine and tenofovir alafenamide 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 emtricitabine and tenofovir alafenamide 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 Precautions).
In a study in virologically suppressed adult patients measures of tubular proteinuria were similar in patients switching to a regimen containing emtricitabine and tenofovir alafenamide 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 emtricitabine and tenofovir alafenamide 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.
Pharmacokinetics: 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 emtricitabine and tenofovir alafenamide fumarate 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 1.15. 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 hydrolyzed 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 eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion.
Pharmacokinetics in special population: 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 4). (See Table 4.)
Click on icon to see table/diagram/imageRenal 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 but <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 (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 Adverse Reactions).
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.
Toxicology: Preclinical safety data: Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Emtricitabine has demonstrated low carcinogenic potential in mice and rats.
Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primary target organs of toxicity. Bone toxicity was observed as reduced BMD in rats and dogs at tenofovir exposures at least four times greater than those expected after administration of emtricitabine and tenofovir alafenamide fumarate. A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovir exposures of approximately 4 and 17 times greater, respectively, than those expected after administration of emtricitabine and tenofovir alafenamide fumarate.
Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.
Because there is a lower tenofovir exposure in rats and mice after the administration of tenofovir alafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies and a rat peri-postnatal study were conducted only with tenofovir disoproxil fumarate. No special hazard for humans was revealed in conventional studies of carcinogenic potential and toxicity to reproduction and development. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or fetal parameters. However, tenofovir disoproxil fumarate reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.
