Emtricitabine Propofol Tenofovir Tablets (II) Instructions

PI = Protease Inhibitor

a Week 48 window is defined as day 294 to day 377 inclusive.

b The 96th week window is from the 630th to the 713th (inclusive).

c Includes patients with a Week 48 or Week 96 window of ≥ 50 copies/mL; patients discontinued early due to lack of efficacy or loss of efficacy; patients discontinued early due to adverse events (AEs), death, or lack of efficacy Patients who discontinued for reasons other than adverse events (AEs), death, or lack of efficacy or loss of efficacy and had a viral value ≥ 50 copies/mL at the time of discontinuation.

d Includes patients who discontinued treatment due to an AE or death that resulted in no treatment period virologic data for the specified window at any time point between window 1 and time.

e Includes patients who discontinued treatment for reasons other than AE, death, or lack of efficacy or loss of efficacy, such as withdrawal of consent, missed visits, etc.

In study GS-US-311-1717, patients who achieved virologic suppression (HIV-1 RNA < 50 copies/mL) while receiving at least 6 months of an abacavir/lamivudine containing regimen were randomized in a 1:1 ratio to switch to emtricitabine propofol tenofovir (N= 280) while maintaining the third drug at baseline unchanged or continue to receive the baseline regimen containing abacavir/lamivudine (N= 276).

Patients were stratified by the category of third drug in the previous regimen. At baseline, 30% of patients were receiving abacavir/lamivudine in combination with an enhancing protease inhibitor and 70% were receiving abacavir/lamivudine in combination with a non-enhancing third drug. Virologic success rates at week 48 were as follows: treatment regimen containing emtricitabine-propofol tenofovir: 89.7% (227/253 subjects); treatment regimen containing abacavir/lamivudine: 92.7% (230/248 subjects). At week 48, conversion to an emtricitabine-containing propofol tenofovir regimen was noninferior to continuation on the baseline abacavir/lamivudine-containing regimen in maintaining HIV-1 RNA < 50 copies/mL.

Patients with HIV-1 infection with mild to moderate renal impairment

In study GS-US-292-0112, 242 HIV-1-infected patients with mild to moderate renal impairment (eGFR_CG: 30-69 mL/min) were converted to treatment with emtricitabine propofol tenofovir (10 mg) in combination with everolimus and cobicistat as a fixed-dose combination tablet. An open-label clinical study evaluated the efficacy and safety of emtricitabine propofol tenofovir. Patients achieved virologic suppression (HIV-1 RNA < 50 copies/mL) at least 6 months prior to switching therapy.

The mean age was 58 years (range: 24-82 years), with 63 patients (26%) aged ≥ 65 years. 79% were male, 63% were white, 18% were black, and 14% were Asian. 13% of patients were identified as Hispanic/Latino. At baseline, median eGFR was 56 mL/min and 33% of patients had an eGFR of 30-49 mL/min. mean baseline CD4+ cell count was 664 cells/mm³ (range: 1261,813).

At week 144, 88.1% of patients (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching to treatment with emtricitabine propofol tenofovir in combination with everolimus and cobicistat as a fixed-dose combination tablet.

Patients with HIV and HBV co-infection

In the open-label study GS-US-292-1249, the efficacy and safety of emtricitabine propofol tenofovir combined with everolimus and cobicistat as a fixed-dose combination tablet (E/C/F/TAF) was evaluated in adult patients with HIV-1 and chronic hepatitis B coinfection. 69/72 patients had received prior TDF-containing anti-retroviral therapy. retroviral therapy. At the start of E/C/F/TAF treatment, 72 patients had achieved HIV suppression (HIV-1 RNA < 50 copies/mL) for at least 6 months, had suppressed or not suppressed HBV DNA, and had compensated liver function. The mean age was 50 years (range 28-67 years), 92% of patients were male, 69% were white, 18% were black, and 10% were of Asian descent. The mean baseline CD4+ cell count was 636 cells/mm³ (range, 2631498). At baseline 86% of patients (62/72) were HBV-suppressed (HBV DNA < 29 IU/mL) and 42% (30/72) were HBeAg-positive.

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

At week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after conversion to emtricitabine propofol tenofovir combined with everolimus and cobicistat as a fixed-dose combination tablet therapy. the mean change in CD4+ cell count at week 48 relative to baseline was -2 cells/mm³. At week 48, the use of missing= failure analysis yielded HBV DNA < 29 IU/mL in 92% of patients (66/72 patients). of the 62 patients with HBV suppression at baseline, 59 remained suppressed and 3 had missing data. Of the 10 patients whose HBV was not suppressed (HBV DNA ≥ 29 IU/mL) at baseline, 7 became suppressed, 2 remained detectable, and 1 had missing data.

There are limited clinical data on E/C/F/TAF dosing in patients with primary HIV/HBV coinfection.

Change in bone mineral density measures

In the primary treatment patient study, after 144 weeks of treatment, analysis using dual-energy X-ray absorptiometry (DXA) for the hip (mean change: -0.8% vs -3.4%, p < 0.001) and lumbar spine (mean change: -0.9% vs -3.0%, p < 0.001) showed that emtricitabine propofol tenofovir with everolimus and cobicistat in a fixed-dose combination tablet group showed a smaller decrease in bone mineral density (BMD) than in the E/C/F/TDF group. In a separate study, BMD (measured using DXA analysis of the hip and lumbar spine) also decreased less after 48 weeks of treatment with emtricitabine propofol tenofovir with a fixed-dose combination tablet of darunavir and cobicistat compared with the darunavir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate treatment groups.

In the study of adult patients who achieved virologic suppression, DXA analysis of the hip (mean change relative to baseline 1.9% vs -0.3%, p < 0.001) and lumbar spine (mean change relative to baseline 2.2% vs -0.2%, p < 0.001) showed that switching from a TDF-containing regimen to emtricitabine BMD improvement was observed during 96 weeks of treatment after binaprofen tenofovir, compared with only a small change in maintaining the TDF-containing regimen.

In the study of adult patients who achieved virologic suppression, DXA analysis of the hip (mean change relative to baseline 0.3% vs 0.2%, p = 0.55) and lumbar spine (mean change relative to baseline 0.1% vs < 0.1%, p = 0.78) showed that compared with maintenance of the abacavir/lamivudine containing regimen, switching from the abacavir/lamivudine containing BMD did not change significantly during 48 weeks of treatment after switching from an abacavir/lamivudine regimen to an emtricitabine propofol tenofovir regimen.

Change in renal function measures

In the primary treatment arm of the study, there was less impact on renal safety parameters after 144 weeks of treatment with emtricitabine propofol tenofovir compared with E/C/F/TDF with fixed-dose combination tablets of everolimus and cobicistat (measured by eGFR_CG and urinary protein to creatinine ratio after 144 weeks of treatment and by urinary albumin to creatinine ratio after 144 weeks of treatment as measured by the urinary albumin-to-creatinine ratio). No subjects discontinued E/C/F/TAF during 144 weeks of treatment because of renal adverse events that occurred during the treatment period, compared with 12 subjects who discontinued E/C/F/TDF (p < 0.001).

In a separate study in primary care patients, treatment with emtricitabine propofol tenofovir with a fixed-dose combination tablet of darunavir and cobicistat had less impact on renal safety parameters after 48 weeks compared with darunavir and cobicistat combined with emtricitabine/tenofovir dipivoxil fumarate (see [Caution]).

In the study of adult patients who achieved virologic suppression, measures of renal tubular proteinuria in patients who switched to an emtricitabine-containing propofol tenofovir regimen were similar to those who continued to receive the baseline abacavir/lamivudine containing regimen. At week 48, the median percentage change in the ratio of urinary retinol-binding protein to creatinine in the emtricitabine propofol tenofovir group was 4%, with a corresponding value of 16% in patients maintained on the abacavir/lamivudine containing regimen; the corresponding value for the ratio of urinary β-2 microglobulin to creatinine was 4% vs 5%.

Pediatric population

In study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine propofol tenofovir (10 mg) were evaluated in an open-label study of 50 primary HIV-1-infected adolescents treated with emtricitabine propofol tenofovir (10 mg) in combination with a fixed-dose combination tablet of everolimus and cobicistat. The mean age of the patients was 15 years (range: 12-17 years), 56% were female, 12% were Asian, and 88% were black. At baseline, the median plasma HIV-1 RNA was 4.7 log₁₀ copies/mL, the median CD4+ cell count was 456 cells/mm³ (range: 95-1,110), and the median CD4+% was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 RNA > 100,000 copies/mL. at week 48, 92% (46/50) of patients achieved HIV-1 RNA < 50 copies/mL, a response rate similar to that seen in studies of primed HIV-1-infected adult patients. At week 48, the mean increase in CD4+ cell count relative to baseline was 224 cells/mm³. Up to week 48, no resistance to E/C/F/TAF was detected.

[Pharmacology and Toxicology

Pharmacology

Mechanism of action

Entricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a nucleoside analogue of 2′-deoxycytidine. Emtricitabine is phosphorylated by cytase to form emtricitabine triphosphate. Emtricitabine triphosphate is integrated into viral deoxyribonucleic acid (DNA) with the help of HIV reverse transcriptase (RT) (leading to DNA strand termination), thereby inhibiting HIV replication. Emtricitabine is active against HIV-1, HIV-2, and HBV.

Propofol tenofovir is a nucleotide reverse transcriptase inhibitor (NtRTI) and a phosphoramidite drug precursor (2′-deoxyadenosine monophosphate analogue) of tenofovir. Propofol tenofovir penetrates cells and is more effective than tenofovir dipivoxil fumarate in increasing tenofovir concentrations in peripheral blood mononuclear cells (PBMC) or HIV target cells, including lymphocytes and macrophages, due to increased plasma stability and intracellular activation through hydrolysis by histone A. Intracellular tenofovir subsequently undergoes phosphorylation to form the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate is embedded in viral DNA by means of HIV RT integration (leading to DNA strand termination), thereby inhibiting HIV replication.

Tenofovir is active against HIV-1, HIV-2, and HBV.

In vitro antiviral activity

In cell culture, emtricitabine propofol tenofovir showed synergistic antiviral activity. No antagonistic effects of emtricitabine or propofol tenofovir were observed when combined with other anti-retroviral drugs.

The antiviral activity of emtricitabine was evaluated in lymphoblastoid cell lines, MAGI CCR5 cell lines, and PBMC against laboratory and clinical isolates of HIV-1. The 50% effective concentration (EC₅₀) values of emtricitabine ranged from 0.0013 to 0.64 µM. In cell culture, emtricitabine showed antiviral activity against HIV-1 subtypes A, B, C, D, E, F, and G (EC₅₀ values ranged from 0.007 to 0.075 µM) and showed specific activity against HIV-2 virus strains (EC₅₀ values range from 0.007 to 1.5 µM) with specific activity.

The antiviral activity of propofol tenofovir against HIV-1 subtype B laboratory and clinical isolates was evaluated in lymphoblastoid cell lines, PBMC, primary monocytes/macrophages, and CD4+-T lymphocytes. The EC₅₀ values of propofol tenofovir ranged from 2.0 to 14.7 nM. In cell culture, propofol tenofovir showed antiviral activity against all HIV-1 groups (M, N, and O, including subtypes A, B, C, D, E, F, and G) (EC₅₀ values ranging from 0.10 to 12.0 nM) and showed strain-specific activity against HIV-2 (EC₅₀ values range from 0.91 to 2.63 nM).

Drug resistance

In vitro

Decreased susceptibility to emtricitabine was associated with the M184V/I mutation in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to propofol tenofovir expressed the K65R mutation in HIV-1 RT; in addition, the K70E mutation was observed in HIV-1 RT for a short time.

Primary treatment

In a pooled analysis of patients in phase 3 studies GS-US-292-0104 and GS-US-292-0111 who received emtricitabine propofol tenofovir (10 mg) in combination with everolimus and cobicistat fixed-dose combination tablets who had not received antiretroviral therapy, there was a significant reduction in the number of patients with confirmed virologic failure, week 144, or early Plasma HIV-1 isolates from all patients with HIV-1 RNA ≥ 400 copies/mL at discontinuation of study drug were genotyped. By week 144, the presence of one or more primary emtricitabine, propofol tenofovir, or everolimus resistance-associated mutations was observed in HIV-1 isolates isolated from 12/22 patients with evaluable genotype data for paired baseline and E/C/F/TAF treatment-naïve isolates (12/866 patients [1.4%]), compared with the presence of one or more primary emtricitabine, propofol tenofovir, or everolimus resistance-associated mutations in the E/C/F/ TDF group was observed in 12/20 treatment failure isolates (12/867 patients [1.4%]). In the E/C/F/TAF group, the mutations present in RT were M184V/I (n = 11) and K65R (n = 2) and in integrase were T66T/A/I/V (n = 2), E92Q (n = 4), Q148Q/R (n = 1) and N155H (n = 2). Among the HIV-1 isolates isolated from the 12 patients in the E/C/F/TDF group who developed drug resistance, the mutations appearing in RT were M184V/I (n = 9) and K65R/N (n = 4) and L210W (n = 1), and the mutations appearing in integrase were E92Q/V (n = 4) and Q148R (n = 2) and N155H/S (n = 3). The majority of HIV-1 isolates from patients in both treatment groups who developed integrase everolimus resistance mutations also developed emtricitabine resistance mutations in RT.

Patients with HIV and HBV coinfection

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

Cross-resistance in HIV-1-infected patients with primary treatment or suppressed virologic features

Entricitabine-resistant viruses with M184V/I substitutions are cross-resistant to lamivudine but retain susceptibility to desoxymethyldeoxyinosine, stavudine, tenofovir, and zidovudine.

K65R and K70E mutations reduce susceptibility to abacavir, dehydroxymyosine, lamivudine, emtricitabine, and tenofovir, but retain susceptibility to zidovudine.

Polynucleoside-resistant HIV-1 with the T69S double insertion mutation or the Q151M mutation complex (including K65R) has reduced susceptibility to ciprofloxacin tenofovir.

Non-clinical toxicology

Nonclinical data for emtricitabine indicate no specific hazard in humans based on routine studies of safety pharmacology, repeated dosing toxicity, genotoxicity, carcinogenic potential, and reproductive and developmental toxicity. In mice and rats, the carcinogenic potential of emtricitabine is low.

Nonclinical studies of tenofovir in rats and dogs have shown that bone and kidney are the primary target organs for toxicity. This osteo-toxicity reduction in BMD was observed in rats and dogs at tenofovir exposures at least four times the expected exposure after emtricitabine propofol tenofovir administration. Very mild histiocytic infiltration was observed in the canine eye when propofol tenofovir and tenofovir exposure was approximately 4 and 17 times the expected exposure after emtricitabine propofol tenofovir administration, respectively.

Propofol tenofovir was not mutagenic or chromosome-breaking in routine genotoxicity analyses.

Because of the lower exposure to tenofovir in rats and mice after propofol tenofovir administration compared with tenofovir disoproxil fumarate, only a carcinogenicity study and a perinatal-postnatal study in rats were performed using tenofovir disoproxil fumarate. Routine studies of carcinogenic potential and reproductive and developmental toxicity showed no specific hazard to humans. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or fetal litter parameters. However, in a perinatal-postnatal toxicity study at maternal toxicity doses, tenofovir disoproxil fumarate reduced the viability index and body weight of the pups.

[Pharmacokinetics].

Absorption

After oral administration, emtricitabine was rapidly and extensively absorbed, reaching peak plasma concentrations 1 to 2 hours after dosing. steady-state peak plasma concentrations (C_max) (mean ± SD) of emtricitabine were 1.8 ± 0.7 μg/mL in 20 HIV-1-infected subjects after multiple oral doses of emtricitabine, and 24-hour dosing The area under the plasma concentration-time curve (AUC) for the interval (mean ± SD) was 10.0 ± 3.1 μg-h/mL. the mean steady-state plasma trough concentration 24 hours after dosing was equal to or greater than the mean in vitro IC90 value for anti-HIV-1 activity.

Enterceptor systemic exposure was not affected when emtricitabine was given with food.

Peak plasma concentrations were observed approximately 1 hour after administration of emtricitabine in the form of emtricitabine propofol tenofovir (25 mg) or E/C/F/TAF (10 mg) in healthy subjects after feeding. The mean (mean ± SD) C_max and AUC_last were 0.21 ± 0.13 μg/mL and 0.25 ± 0.11 μg-h/mL, respectively, after a single dose of 25 mg of propofol tenofovir in the form of emtricitabine propofol in the fed state. fed After a single dose of 10 mg propofol tenofovir in the E/C/F/TAF form in the state, the mean (mean± SD) C_max and AUC_last were 0.21 ± 0.10 μg/mL and 0.25 ± 0.08 μg-h/mL, respectively.

Compared with dosing in the fasted state, administration of propofol tenofovir with a high-fat meal (approximately 800 kcal, 50% fat) resulted in a decrease in propofol tenofovir C_max (1537%) and an increase in AUC_last (1777%).

Distribution

The in vitro binding of emtricitabine to human plasma proteins < 4% and was independent of drug concentration in the range of 0.02200 µg/mL. At peak plasma concentrations, the mean plasma-to-blood drug concentration ratio was approximately 1.0 and the mean semen-to-plasma drug concentration ratio was approximately 4.0.

The in vitro binding rate of tenofovir to human plasma proteins < 0.7% and was unaffected by drug concentration in the 0.0125 μg/mL range. The in vitro binding of propofol tenofovir to human plasma proteins was approximately 80% in samples collected during the clinical study.

Biotransformation

In vitro studies have shown that emtricitabine is not an inhibitor of human CYP enzymes. The full dose of [¹⁴C]-emtricitabine was recovered in urine (~86%) and feces (~14%) after emtricitabine administration. Thirteen percent of the dose was recovered in urine as the three putative metabolites. Biotransformation of emtricitabine included partial oxidation of thiols to form 3′-sulfoxide diastereoisomers (~9% of the dose) and binding to glucuronide to form 2′-O-glucuronide (~4% of the dose). No other metabolites were identified.

Metabolism is the primary route of elimination of propofol tenofovir in humans, accounting for > 80% of the oral dose. In vitro studies have shown that propofol tenofovir is metabolized to tenofovir (the major metabolite) by histone proteinase A in PBMCs (including lymphocytes and other HIV target cells) and macrophages and by carboxylesterase-1 in hepatocytes. In in vivo, intracellular hydrolysis of propofol tenofovir generates tenofovir (the major metabolite), which is phosphorylated to form the active metabolite tenofovir diphosphate. In human clinical studies, a 10-mg oral dose of propofol tenofovir (in combination with emtricitabine and everolimus and cobicistat) produced more than four times the concentration of tenofovir diphosphate in PBMC compared with tenofovir dipivoxil (as fumarate) at 245 mg oral dose (in combination with emtricitabine and everolimus and cobicistat), and the plasma tenofovir concentrations were more than 90% lower than those of the former.

In in vitro, propofol tenofovir is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Very small amounts of propofol tenofovir are metabolized by CYP3A4. Propofol tenofovir exposure was not significantly affected when combined with the moderate CYP3A inducer probe efavirenz. After propofol tenofovir administration, plasma [¹⁴C]radioactivity exhibited a time-dependent profile, with propofol tenofovir being the most abundant species during the first few hours and uric acid during the rest of the time.

Elimination

Emtricitabine is primarily excreted renally, with the full dose recovered in urine (about 86%) and feces (about 14%). Thirteen percent of the emtricitabine dose was recovered in the urine as three metabolites. The mean systemic clearance of emtricitabine was 307 mL/min. After oral administration, the elimination half-life of emtricitabine was approximately 10 hours.