Emtricitabine/tenofovir disoproxil fumarate Actions

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Actions of Emtricitabine/tenofovir disoproxil fumarate in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Emtricitabine and tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs FTC and TDF.

Emtricitabine/tenofovir disoproxil fumarate pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.

Mechanism of Action

Emtricitabine and tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs FTC and TDF.

Pharmacokinetics

Emtricitabine and tenofovir disoproxil fumarate tablet: One emtricitabine and tenofovir disoproxil fumarate tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine: The pharmacokinetic properties of FTC are summarized in Table 8. Following oral administration of FTC, FTC is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of FTC, the plasma FTC half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of TDF are summarized in Table 8. Following oral administration of TDF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70% to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of TDF, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 8 Single Dose Pharmacokinetic Parameters for FTC and Tenofovir in Adultsa

FTC

Tenofovir

Fasted

Oral Bioavailabilityb (%)

92 (83.1 to 106.4)

25 (NC to 45.0)

Plasma Terminal Elimination Half-Lifeb (hr)

10 (7.4 to 18.0)

17 (12.0 to 25.7)

Cmaxc (mcg/mL)

1.8±0.72d

0.30±0.09

AUCc (mcg·hr/mL)

10.0±3.12d

2.29±0.69

CL/Fc (mL/min)

302±94

1043±115

CLrenalc (mL/min)

213±89

243±33

a. NC=Not calculated

b. Median (range)

c. Mean (± SD)

d. Data presented as steady-state values

Effects of Food on

Oral Absorption

Emtricitabine and tenofovir disoproxil fumarate may be administered with or without food. Administration of emtricitabine and tenofovir disoproxil fumarate following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and Cmax) were unaffected when emtricitabine and tenofovir disoproxil fumarate was administered with either a high fat or a light meal.

Specific Populations

Race

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.

Gender

Emtricitabine and Tenofovir Disoproxil Fumarate: FTC and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

Treatment of HIV-1 Infection: The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate in pediatric subjects weighing 17 kg and above are not available. The dosage recommendations of emtricitabine and tenofovir disoproxil fumarate in this population are based on the dosage recommendations of FTC and TDF in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients.

HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.

Geriatric Patients

Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Renal Impairment

The pharmacokinetics of FTC and tenofovir are altered in subjects with renal impairment. In adult subjects with creatinine clearance below 50 mL/min, Cmax and AUC0-∞ of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment.

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of TDF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate or FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady-state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low.

TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is co-administered with an inhibitor of these transporters, an increase in absorption may be observed.

No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, stavudine, TDF, and zidovudine (Tables 9 and 10). Similarly, no clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 11 and 12).

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Co-administered Druga

Co-administered

Drug

Dose of Co-administered

Drug (mg)

FTC

Dose (mg)

N

% Change of FTC Pharmacokinetic Parametersb (90% CI)

Cmax

AUC

Cmin

TDF

300 once daily

x 7 days

200 once daily

x 7 days

17

↑20

(↑12 to ↑29)

Zidovudine

300 twice daily

x 7 days

200 once daily

x 7 days

27

Indinavir

800 x 1

200 x 1

12

NA

Famciclovir

500 x 1

200 x 1

12

NA

Stavudine

40 x 1

200 x 1

6

NA

a. All interaction trials conducted in healthy volunteers

b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of FTCa

Co-administered

Drug

Dose of Co-administered Drug (mg)

FTC

Dose (mg)

N

% Change of Co-administered Drug Pharmacokinetic Parametersb

(90% CI)

Cmax

AUC

Cmin

TDF

300 once daily

x 7 days

200 once daily

x 7 days

17

Zidovudine

300 twice daily

x 7 days

200 once daily

x 7 days

27

↑ 17

(↑ 0 to ↑ 38)

↑ 13

(↑ 5 to ↑ 20)

Indinavir

800 x 1

200 x 1

12

NA

Famciclovir

500 x 1

200 x 1

12

NA

Stavudine

40 x 1

200 x 1

6

NA

a. All interaction trials conducted in healthy volunteers

b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Co-administered Drug

Co-administered Drug

Dose of Co-administered Drug (mg)

N

% Change of Tenofovir Pharmacokinetic Parametersb (90% CI)

Cmax

AUC

Cmin

Atazanavirc

400 once daily × 14 days

33

­↑ 14

(↑ 8 to ↑ 20)

­

↑ 24

(↑ 21 to ↑ 28)

­

↑ 22

(↑ 15 to ↑ 30)

Atazanavir/ Ritonavirc

300/100 once daily

12

­↑ 34

(↑ 20 to ↑ 51)

­

↑ 37

(↑ 30 to ↑ 45)

­

↑ 29

(↑ 21 to ↑ 36)

Darunavir/ Ritonavird

300/100 twice daily

12

­

↑ 24

(↑ 8 to ↑ 42)

­

↑ 22

(↑ 10 to ↑ 35)

­

↑ 37

(↑ 19 to ↑ 57)

Indinavir

800 three times daily × 7 days

13

↑ 14

(↓ 3 to ↑ 33)

Ledipasvir/ Sofosbuvire,f

90/400 once daily × 10 days

24

­

↑ 47

(↑ 37 to ↑ 58)

­

↑ 35

(↑ 29 to ↑ 42 )

­

↑ 47

(↑ 38 to ↑ 57)

Ledipasvir/ Sofosbuvire,g

23

­

↑ 64

(↑ 54 to ↑ 74)

­

↑ 50

(↑ 42 to ↑ 59)

­

↑ 59

(↑ 49 to ↑ 70)

Ledipasvir/ Sofosbuvirh

90/400 once daily × 14 days

15

­

↑ 79

(↑ 56 to ↑ 104)

­

↑ 98

(↑ 77 to ↑ 123)

­

↑ 163

(↑ 132 to ↑ 197)

Ledipasvir/ Sofosbuviri

90/400 once daily × 10 days

14

­

↑ 32

(↑ 25 to ↑ 39 )

­

↑ 40

(↑ 31 to ↑ 50 )

­

↑ 91

(↑ 74 to ↑ 110)

Ledipasvir/ Sofosbuvirj

90/400 once daily × 10 days

29

­

↑ 61

(↑ 51 to ↑ 72 )

­

↑ 65

(↑ 59 to ↑ 71 )

­

↑ 115

(↑ 105 to ↑ 126)

Lopinavir/ Ritonavir

400/100 twice daily × 14 days

24

­

↑ 32

(↑ 25 to ↑ 38)

­

↑ 51

(↑ 37 to ↑ 66)

Saquinavir/ Ritonavir

1000/100 twice daily × 14 days

35

­

↑ 23

(↑ 16 to ↑ 30)

Sofosbuvirk

400 single dose

16

­

↑ 25

(↑ 8 to ↑ 45)

Sofosbuvir/ Velpatasvirl

400/100 once daily

24

­ ↑ 44

(­ ­­­­­↑ 33 to ↑ ­ 55)

­ ↑ 40

(­ ↑ 34 to ↑­ 46)

­↑ 84

(­ ↑ 76 to ↑­ 92)

Sofosbuvir/ Velpatasvirm

400/100 once daily

30

­ ↑ 46

(­ ↑ 39 to ­ ↑ 54)

­ ↑ 40

(­ ↑ 34 to ↑­ 45)

­ ↑ 70

(­ ↑ 61 to ­ ↑ 79)

Sofosbuvir/ Velpatasvir/ Voxilaprevirn

400/100/100 + Voxilapreviro 100 once daily

29

­ ↑ 48

(­ ↑ 36 to ­ ↑ 61)

­ ↑ 39

(­ ↑ 32 to ↑­ 46)

­ ↑ 47

(­ ↑ 38 to ­ ↑ 56)

Tacrolimus

0.05 mg/kg twice daily × 7 days

21

­ ↑ 13

(­ ↑ 1 to ­ ↑ 27)

Tipranavir/ Ritonavirp

500/100 twice daily

22

↓ 23

(↓ 32 to ↓ 13)

↓ 2

(↓ 9 to ­ ↑5)

­↑ 7

(↓ 2 to ­ ↑ 17)

750/200 twice daily (23 doses)

20

↓ 38

(↓ 46 to ↓ 29)

­ ↑ 2

(↓ 6 to ­ ↑ 10)

­ ↑ 14

(­ ↑ 1 to ­ ↑ 27)

a. Subjects received VIREAD 300 mg once daily.

b. Increase = ­↑; Decrease = ↓; No Effect =⇔

c. Reyataz Prescribing Information.

d. Prezista Prescribing Information.

e. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results.

f. Comparison based on exposures when administered as atazanavir/ritonavir + FTC/TDF.

g. Comparison based on exposures when administered as darunavir/ritonavir + FTC/TDF.

h. Study conducted with ATRIPLA (efavirenz/FTC/TDF) co-administered with HARVONI.

i. Study conducted with COMPLERA (FTC/rilpivirine/TDF) co-administered with HARVONI.

j. Study conducted with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) + dolutegravir co-administered with HARVONI.

k. Study conducted with ATRIPLA co-administered with SOVALDI® (sofosbuvir).

l. Study conducted with COMPLERA co-administered with EPCLUSA; co-administration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD, emtricitabine and tenofovir disoproxil fumarate + atazanavir/ritonavir, or emtricitabine and tenofovir disoproxil fumarate + darunavir/ritonavir.

m. Administered as raltegravir + FTC/TDF.

n. Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF.

o. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients

p. Aptivus Prescribing Information.

No effect on the pharmacokinetic parameters of the following co-administered drugs was observed with emtricitabine and tenofovir disoproxil fumarate: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine.

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tenofovir

Co-administered Drug

Dose of Co-administered Drug (mg)

N

% Change of Co-administered Drug Pharmacokinetic Parametersa

(90% CI)

Cmax

AUC

Cmin

Abacavir

300 once

8

↑ 12

(↓ 1 to ↑ 26)

NA

Atazanavirb

400 once daily x 14 days

34

↓ 21

(↓ 27 to ↓ 14)

↓ 25

(↓ 30 to ↓ 19)

↓ 40

(↓ 48 to ↓ 32)

Atazanavirb

Atazanavir/Ritonavir 300/100 once daily x 42 days

10

↓ 28

(↓ 50 to ↑ 5)

↓ 25c

(↓ 42 to ↓ 3)

↓ 23c

(↓ 46 to ↑ 10)

Darunavird

Darunavir/Ritonavir 300/100 once daily

12

↑ 16

(↓ 6 to ↑ 42)

↑ 21

(↓ 5 to ↑ 54)

↑ 24

(↓ 10 to ↑ 69)

Didanosinee

250 once, simultaneously with TDF and a light mealf

33

↓ 20g

(↓ 32 to ↓ 7)

⇔g

NA

Emtricitabine

200 once daily x 7 days

17

↑ 20

(↑ 12 to ↑ 29)

Indinavir

800 three times daily x 7 days

12

↓ 11

(↓ 30 to ↑ 12)

Entecavir

1 once daily x 10 days

28

↑ 13

(↑ 11 to ↑ 15)

Lamivudine

150 twice daily x 7 days

15

↓ 24

(↓ 34 to ↓ 12)

Lopinavir

Ritonavir

Lopinavir/Ritonavir 400/100 twice daily x 14 days

24

Saquinavir

Ritonavir

Saquinavir/Ritonavir 1000/100 twice daily x 14 days

32

↑ 22

(↑ 6 to ↑41)

↑ 29h

(↑ 12 to ↑ 48)

↑ 47h

(↑ 23 to ↑ 76)

↑ 23

(↑ 3 to ↑ 46)

Tacrolimus

0.05 mg/kg twice daily x 7 days

21

Tipranaviri

Tipranavir/Ritonavir 500/100 twice daily

22

↓ 17

(↓ 26 to ↓ 6)

↓ 18

(↓ 25 to ↓ 9)

↓ 21

(↓ 30 to ↓ 10)

Tipranavir/Ritonavir 750/200 twice daily (23 doses)

20

↓ 11

(↓ 16 to ↓ 4)

↓ 9

(↓ 15 to ↓ 3)

↓ 12

(↓ 22 to 0)

a. Increase =↑­; Decrease = ↓; No Effect = ⇔; NA = Not Applicable

b. Reyataz Prescribing Information.

c. In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg resulted in AUC and Cmin values of atazanavir that were 2.3-and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.

d. Prezista Prescribing Information.

e. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

f. 373 kcal, 8.2 g fat

g. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.

h. Increases in AUC and Cmin are not expected to be clinically relevant; hence, no dose adjustments are required when TDF and ritonavir-boosted saquinavir are co-administered.

i. Aptivus Prescribing Information.

Microbiology

Mechanism of Action

Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate (FTC-TP), which inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. FTC-TP is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir Disoproxil Fumarate: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), which inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′triphosphate and, after incorporation into DNA, by DNA chain termination. TFV-DP is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity

Emtricitabine and Tenofovir Disoproxil Fumarate: No antagonism was observed in combination studies evaluating the cell culture antiviral activity of FTC and tenofovir together.

Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for FTC were in the range of 0.0013 to 0.64 μM (0.0003 to 0.158 mcg/mL). In drug combination studies of FTC with nucleoside RT inhibitors (abacavir, lamivudine, stavudine, zidovudine), non-nucleoside RT inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. 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).

Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells, and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04 to 8.5 μM. In drug combination studies of tenofovir with nucleoside RT inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine), non-nucleoside RT inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 to 2.2 μM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).

Prophylactic Activity in a Nonhuman Primate Model of HIV-1 Transmission

Emtricitabine and Tenofovir Disoproxil Fumarate: The prophylactic activity of the combination of daily oral FTC and TDF was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral FTC and TDF remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.

Resistance

Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of FTC and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In addition, a K70E substitution in the HIV-1 RT has been selected by tenofovir and results in reduced susceptibility to tenofovir.

In Study 934, a clinical trial of treatment-naïve subjects, resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to FTC and lamivudine, was observed in 2/19 analyzed subject isolates in the FTC+TDF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R or K70E substitution in their HIV-1 as analyzed through standard genotypic analysis.

Emtricitabine: FTC-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to FTC was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir.

In treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the TDF arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing TDF through Week 96 showed greater than 1.4-fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a K65R amino acid substitution in the HIV-1 RT.

iPrEx Trial: In the iPrEx trial, a clinical trial of HIV-1 seronegative adult subjects, no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion among 48 subjects in the emtricitabine and tenofovir disoproxil fumarate group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with resistance to FTC were observed in 3 of the 10 subjects (2 of 2 in the emtricitabine and tenofovir disoproxil fumarate group and 1 of 8 in the placebo group). One of the two subjects in the emtricitabine and tenofovir disoproxil fumarate group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment.

Partners PrEP Trial: In the Partners PrEP trial, a clinical trial of HIV-1 seronegative adult subjects, no variants expressing amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion among 12 subjects in the emtricitabine and tenofovir disoproxil fumarate group, 15 subjects in the TDF group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the emtricitabine and tenofovir disoproxil fumarate group, 5 in the TDF group, and 6 in the placebo group). One of the three subjects in the emtricitabine and tenofovir disoproxil fumarate group who was infected with wild type virus at enrollment selected an M184V expressing virus by Week 12. Two of the five subjects in the TDF group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment developed a K65R substitution by Week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at Week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrollment, 4 subjects (2 in the TDF group, 1 in the emtricitabine and tenofovir disoproxil fumarate group, and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with FTC or TDF and may have been present in the infecting virus.

ATN113 Trial: In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects, no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended emtricitabine and tenofovir disoproxil fumarate dosage.

Cross Resistance

Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain NRTIs has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of FTC and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either FTC or lamivudine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Emtricitabine: FTC-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to the NRTIs didanosine, stavudine, tenofovir, and zidovudine, and to NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to FTC.

Tenofovir Disoproxil Fumarate: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to FTC and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R or K70E substitutions. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.


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References

  1. DailyMed. "EMTRICITABINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. DailyMed. "EMTRICITABINE; RILPIVIRINE HYDROCHLORIDE; TENOFOVIR DISOPROXIL FUMARATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  3. NCIt. "Tenofovir Disoproxil Fumarate: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).

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