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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Pharmacology:Mechanism of Action:Tenvira is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenvira requires initial diester hydrolysis for conversion to Tenvira and subsequent phosphorylations by cellular enzymes to form Tenvira diphosphate, an obligate chain terminator. Tenvira diphosphate inhibits the activity of human immunodeficiency virus-1 (HIV-1) reverse transcriptase and hepatitis B virus (HBV) polymerase by competing with the natural substrate deoxyadenosine 5'-triphosphate and after incorporation into DNA, by DNA chain termination. Tenvira diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Activity Against Human Immunodeficiency Virus (HIV): The antiviral activity of Tenvira against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The 50% effective concentration (EC50) values for Tenvira were in the range of 0.04-8.5 micromolar. In drug combination studies of Tenvira with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine) and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenvira displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5-2.2 micromolar) and strain specific activity against HIV-2 (EC50 values ranged from 1.6-5 micromolar).
Activity Against Hepatitis B Virus (HBV): The antiviral activity of Tenvira against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for Tenvira ranged from 0.14-1.5 micromolar, with 50% cytotoxicity concentration (CC50) values >100 micromolar. In cell culture combination, antiviral activity studies of Tenvira with the nucleoside, anti-HBV reverse transcriptase inhibitors emtricitabine, entecavir, lamivudine and telbivudine, no antagonistic activity was observed.
Pharmacokinetics:Absorption: Tenvira is a water soluble diester prodrug of the active ingredient Tenvira. The oral bioavailability of Tenvira from Tenovir in fasted subjects is approximately 25%. Following oral administration of a single-dose Tenvira 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1±0.4 hrs. Cmax and area under the concentration-time curve (AUC) values are 0.3±0.09 mcg/mL and 2.29±0.69 mcg·hr/mL, respectively. The pharmacokinetics of Tenvira are dose proportional over a Tenvira dose range of 75-600 mg and are not affected by repeated dosing.
Distribution:In vitro binding of Tenvira to human plasma or serum proteins is <0.7% and 7.2%, respectively, over the Tenvira concentration range 0.01-25 mcg/mL. The volume of distribution at steady state is 1.3±0.6 L/kg and 1.2±0.4 L/kg, following IV administration of Tenvira 1 mg/kg and 3 mg/kg.
Metabolism and Elimination:In vitro studies indicate that neither Tenvira disoproxil nor Tenvira are substrates of cytochrome (CYP) enzymes. Following IV administration of Tenvira, approximately 70-80% of the dose is recovered in the urine as unchanged Tenvira within 72 hrs of dosing. Following single dose, oral administration of Tenvira, the terminal elimination half-life of Tenvira is approximately 17 hrs. After multiple oral doses of ZifamTenovir 300 mg once daily (under fed conditions), 32±10% of the administered dose is recovered in urine over 24 hrs. Tenvira is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on
Oral Absorption:
Administration of Tenvira following a high-fat meal (~700-1000 kCal containing fat 40-50%) increases the oral bioavailability, with an increased Tenvira AUC(0-∞); of approximately 40% and an increased Cmax of approximately 14%. However, administration of Tenvira with a light meal did not have a significant effect on the pharmacokinetics of Tenvira when compared to fasted administration of the drug. Food delays the time to Tenvira Cmax by approximately 1 hr. Cmax and AUC of Tenvira are 0.33±0.12 mcg/mL and 3.32±1.37 mcg·hr/mL following multiple doses of Tenvira 300 mg once daily in the fed state, when meal content was not controlled.
How should I take Tenvira?
Take darunavir, cobicistat, emtricitabine, and Tenvira alafenamide exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
Darunavir, cobicistat, emtricitabine, and Tenvira alafenamide comes with a patient information leaflet. Read and follow these instructions carefully. Read it again each time you refill your prescription in case there is new information. You should talk to your doctor if you have any questions.
Do not change the dose or stop using darunavir, cobicistat, emtricitabine, and Tenvira alafenamide without checking first with your doctor. When your supply of darunavir, cobicistat, emtricitabine, and Tenvira alafenamide is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of darunavir, cobicistat, emtricitabine, and Tenvira alafenamide.
Take darunavir, cobicistat, emtricitabine, and Tenvira alafenamide with food.
If you cannot swallow the tablet whole, you may cut it into two using a tablet cutter. Take both halves of the tablet right away.
Dosing
The dose of darunavir, cobicistat, emtricitabine, and Tenvira alafenamide will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of darunavir, cobicistat, emtricitabine, and Tenvira alafenamide. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
For oral dosage form (tablets):
For treatment of HIV infection:
Adults—1 tablet once a day. Each tablet contains 800 milligrams (mg) of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of Tenvira alafenamide.
Children—Use and dose must be determined by your doctor.
Missed Dose
If you miss a dose of darunavir, cobicistat, emtricitabine, and Tenvira alafenamide, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Tenvira administration
Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Tablets may be administered without regard to meals. Powder should be mixed with 2 to 4 ounces of soft food (applesauce, baby food, yogurt) and swallowed immediately (avoids bitter taste); do not mix in liquid (powder may float on top of the liquid even after stirring). Measure powder using only the supplied dosing scoop.
Tenvira 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
Tenvira DF is an antiviral drug.
Pharmacokinetics
The pharmacokinetics of Tenvira DF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenvira pharmacokinetics are similar between these populations.
Absorption
Tenvira is a water soluble diester prodrug of the active ingredient Tenvira. The oral bioavailability of Tenvira from Tenvira in fasted subjects is approximately 25%. Following oral administration of a single dose of Tenvira 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 mcg/mL and 2.29 ± 0.69 mcg•hr/mL, respectively.
The pharmacokinetics of Tenvira are dose proportional over a Tenvira dose range of 75 to 600 mg and are not affected by repeated dosing.
Distribution
In vitro binding of Tenvira to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the Tenvira concentration range 0.01 to 25 mcg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of Tenvira 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither Tenvira disoproxil nor Tenvira are substrates of CYP enzymes.
Following IV administration of Tenvira, approximately 70 to 80% of the dose is recovered in the urine as unchanged Tenvira within 72 hours of dosing. Following single dose, oral administration of Tenvira, the terminal elimination half-life of Tenvira is approximately 17 hours. After multiple oral doses of Tenvira 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenvira is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on
Oral Absorption
Administration of Tenvira 300 mg tablets following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in Tenvira AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Tenvira with a light meal did not have a significant effect on the pharmacokinetics of Tenvira when compared to fasted administration of the drug. Food delays the time to Tenvira Cmax by approximately 1 hour. Cmax and AUC of Tenvira are 0.33 ± 0.12 mcg/mL and 3.32 ± 1.37 mcg•hr/mL following multiple doses of Tenvira 300 mg once daily in the fed state, when meal content was not controlled.
Special Populations
Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Gender: Tenvira pharmacokinetics are similar in male and female subjects.
Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of Tenvira were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 10). Tenvira exposure achieved in these pediatric subjects receiving oral once daily doses of Tenvira 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of Tenvira 300 mg.
Table 10 Mean (± SD) Tenvira Pharmacokinetic Parameters by Age Groups for HIV-1-infected Pediatric Patients
Dose and Formulation
300 mg Tablet
8 mg/kg
Oral Powder
12 to <18 Years (N=8)
2 to <12 Years (N=23)
Cmax (mcg/mL)
0.38 ± 0.13
0.24 ± 0.13
AUCtau (mcg•hr/mL)
3.39 ± 1.22
2.59 ± 1.06
Tenvira exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of Tenvira 300 mg tablet were comparable to exposures achieved in HIV-1 infected adults and adolescents receiving once-daily doses of 300 mg.
Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Impaired Renal Function: The pharmacokinetics of Tenvira are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of Tenvira were increased (Table 11). It is recommended that the dosing interval for Tenvira be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.
Table 11 Pharmacokinetic Parameters (Mean ± SD) of Tenofovira in Subjects with Varying Degrees of Renal Function
a 300 mg, single dose of Tenvira.
Baseline Creatinine Clearance (mL/min)
>80
(N=3)
50 to 80
(N=10)
30 to 49
(N=8)
12 to 29
(N=11)
Cmax (mcg/mL)
0.34 ± 0.03
0.33 ± 0.06
0.37 ± 0.16
0.60 ± 0.19
AUC0–∞ (mcg•hr/mL)
2.18 ± 0.26
3.06 ± 0.93
6.01 ± 2.50
15.98 ± 7.22
CL/F (mL/min)
1043.7 ± 115.4
807.7 ± 279.2
444.4 ± 209.8
177.0 ± 97.1
CLrenal (mL/min)
243.5 ± 33.3
168.6 ± 27.5
100.6 ± 27.5
43.0 ± 31.2
Tenvira is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenvira, a four-hour hemodialysis session removed approximately 10% of the administered Tenvira dose.
Patients with Hepatic Impairment: The pharmacokinetics of Tenvira following a 300 mg single dose of Tenvira have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in Tenvira pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in Tenvira dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, Tenvira did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of Tenvira, the potential for CYP-mediated interactions involving Tenvira with other medicinal products is low.
Tenvira has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 12 and 13 summarize pharmacokinetic effects of coadministered drug on Tenvira pharmacokinetics and effects of Tenvira on the pharmacokinetics of coadministered drug. Coadministration of Tenvira with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of Tenvira with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with Tenvira, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 13). The mechanism of this interaction is unknown.
No clinically significant drug interactions have been observed between Tenvira and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.
Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug
a. Subjects received Tenvira 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) provide similar results.
f. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/Tenvira DF.
g. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/Tenvira DF.
h Study conducted with ATRIPLA (efavirenz/emtricitabine/Tenvira DF) coadministered with HARVONI.
i. Study conducted with COMPLERA (emtricitabine/rilpivirine/Tenvira DF) coadministered with HARVONI.
j. Study conducted with TRUVADA (emtricitabine/Tenvira DF) + dolutegravir coadministered with HARVONI.
k. Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).
l. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/Tenvira DF.
m. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/Tenvira DF.
n. Study conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir).
o. Study conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/Tenvira DF) coadministered with EPCLUSA.
p. Study conducted with COMPLERA coadministered with EPCLUSA.
q. Administered as raltegravir + emtricitabine/Tenvira DF.
r. Aptivus Prescribing Information.
Coadministered Drug
Dose of Coadministered Drug (mg)
N
% Change of Tenvira Pharmacokinetic Parametersb
(90% CI)
Cmax
AUC
Cmin
Abacavirc
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 x 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 x 14 days
15
↑ 79
(↑ 56 to ↑ 104)
↑ 98
(↑ 77 to ↑ 123)
↑ 163
(↑ 132 to ↑ 197)
Ledipasvir/ Sofosbuviri
90/400 once daily x 10 days
14
↑ 32
(↑ 25 to ↑ 39)
↑ 40
(↑ 31 to ↑ 50)
↑ 91
(↑74 to ↑ 110)
Ledipasvir/ Sofosbuvirj
90/400 once daily x 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
↑ 55
(↑ 43 to ↑ 68)
↑ 30
(↑ 24 to ↑ 36)
↑ 39
(↑ 31 to ↑ 48)
Sofosbuvir/ Velpatasvirm
400/100 once daily
29
↑ 55
(↑ 45 to ↑ 66)
↑ 39
(↑ 33 to ↑ 44)
↑ 52
(↑ 45 to ↑ 59)
Sofosbuvir/ Velpatasvirn
400/100 once daily
15
↑ 77
(↑ 53 to ↑ 104)
↑ 81
(↑ 68 to ↑ 94)
↑ 121
(↑ 100 to ↑ 143)
Sofosbuvir/ Velpatasviro
400/100 once daily
24
↑ 36
(↑ 25 to ↑ 47)
↑ 35
(↑ 29 to ↑ 42)
↑ 45
(↑ 39 to ↑ 51)
Sofosbuvir/ Velpatasvirp
400/100 once daily
24
↑ 44
(↑ 33 to ↑ 55)
↑ 40
(↑ 34 to ↑ 46)
↑ 84
(↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvirq
400/100 once daily
30
↑ 46
(↑ 39 to ↑ 54)
↑ 40
(↑ 34 to ↑ 45)
↑ 70
(↑ 61 to ↑ 79)
Tacrolimus
0.05 mg/kg twice daily
x 7 days
21
↑ 13
(↑1 to ↑ 27)
⇔
⇔
Tipranavir/ Ritonavirr
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)
No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with Tenvira: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.
Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenvira
a. Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable
b. Reyataz Prescribing Information.
c. In HIV-infected subjects, addition of Tenvira DF 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.
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 Tenvira DF and ritonavir-boosted saquinavir are coadministered.
i. Aptivus Prescribing Information.
Coadministered Drug
Dose of Coadministered Drug (mg)
N
% Change of Coadministered Drug Pharmacokinetic Parametersa
(90% CI)
Cmax
AUC
Cmin
Abacavir
300 once
8
↑ 12
(↓1 to ↑ 16)
⇔
NA
Atazanavirb
400 once daily
× 14 days
34
↓ 21
(↓27 to ↓ 14)
↓ 25
(↓30 to ↓ 19)
↓ 40
(↓48 to↓32)
Atazanavirb
Atazanavir/ Ritonavir 300/100 once daily × 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 Tenvira and a light mealf
33
↓ 20g
(↓32 to ↓ 7)
⇔g
NA
Emtricitabine
200 once daily
× 7 days
17
⇔
⇔
↑ 20
(↑12 to ↑ 29)
Entecavir
1 mg once daily
× 10 days
28
⇔
↑ 13
(↑11 to ↑ 15)
⇔
Indinavir
800 three times daily × 7 days
12
↓ 11
(↓30 to ↑12)
⇔
⇔
Lamivudine
150 twice daily
× 7 days
15
↓ 24
(↓34 to ↓ 12)
⇔
⇔
Lopinavir Ritonavir
Lopinavir/
Ritonavir 400/100 twice daily × 14 days
24
⇔
⇔
⇔
Saquinavir
Ritonavir
Saquinavir/
Ritonavir 1000/100 twice daily × 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)
Microbiology
Mechanism of Action
Tenvira DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenvira DF requires initial diester hydrolysis for conversion to Tenvira and subsequent phosphorylations by cellular enzymes to form Tenvira diphosphate, an obligate chain terminator. Tenvira diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenvira diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Activity against HIV
Antiviral Activity
The antiviral activity of Tenvira against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for Tenvira were in the range of 0.04 mcM to 8.5 mcM. In drug combination studies, Tenvira was not antagonistic with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenvira 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 mcM to 2.2 mcM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 mcM to 5.5 mcM).
Resistance
HIV-1 isolates with reduced susceptibility to Tenvira have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2 to 4-fold reduction in susceptibility to Tenvira. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by Tenvira and results in low-level reduced susceptibility to Tenvira.
In Study 903 of treatment-naïve subjects (Tenvira + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the Tenvira arm and in 2/49 (4%) of analyzed patient isolates in the stavudine arm. Of the 8 subjects whose virus developed K65R in the Tenvira arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the Tenvira arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to Tenvira were not identified in this trial.
In Study 934 of treatment-naïve subjects (Tenvira + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis 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 showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 of analyzed subject isolates in the Tenvira + EMTRIVA group and in 10/29 of analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross Resistance
Cross resistance among certain reverse transcriptase inhibitors has been recognized. The K65R and K70E substitutions selected by Tenvira are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to Tenvira.
In Studies 902 and 907 conducted in treatment-experienced subjects (Tenvira + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the Tenvira -treated subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility to Tenvira. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.
The virologic response to Tenvira therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross resistance of Tenvira to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. Tenvira -treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to Tenvira therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to Tenvira therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Tenvira. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to Tenvira was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Studies 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to Tenvira and response to Tenvira therapy. Table 14 summarizes the HIV-1 RNA response by baseline Tenvira susceptibility.
Table 14 HIV-1 RNA Response at Week 24 by Baseline Tenvira Susceptibility (Intent-To-Treat)a
a. Tenvira susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
b. Fold change in susceptibility from wild-type.
c. Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL.
Baseline Tenvira Susceptibilityb
Change in HIV-1 RNAc (N)
<1
–0.74 (35)
>1 and ≤3
–0.56 (49)
>3 and ≤4
–0.3 (7)
>4
–0.12 (9)
Activity against HBV
Antiviral Activity
The antiviral activity of Tenvira against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for Tenvira ranged from 0.14 to 1.5 mcM, with CC50 (50% cytotoxicity concentration) values greater than 100 mcM. In cell culture combination antiviral activity studies of Tenvira with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.
Resistance
Cumulative Tenvira genotypic resistance has been evaluated annually for up to 384 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of Tenvira monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of Tenvira monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on Tenvira monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 15); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to Tenvira (genotypic and phenotypic analyses).
Table 15 Amino Acid Substitutions in Viremic Subjects across HBV Trials of Tenvira
a. Nucleotide-naïve subjects from Studies 0102 (N=246) and 0103 (N=171) receiving up to 384 weeks of treatment with Tenvira.
b. HEPSERA-experienced subjects from Studies 0102/0103 (N=195) and 0106 (N=52) receiving up to 336 weeks of treatment with Tenvira after switching to Tenvira from HEPSERA. Study 0106, a randomized, double-blind, 168-week Phase 2 trial, has been completed.
c. Lamivudine-resistant subjects from Study 0121 (N=136) receiving up to 96 weeks of treatment with Tenvira after switching to Tenvira from lamivudine.
d. Subjects with decompensated liver disease from Study 0108 (N=39) receiving up to 48 weeks of treatment with Tenvira.
e. Denominator includes those subjects who were viremic at last time point on Tenvira monotherapy and had evaluable paired genotypic data.
f. Of the 18 subjects with treatment-emergent amino acid substitutions during Studies 0102 and 0103, 5 subjects had substitutions at conserved sites and 13 subjects had substitutions only at polymorphic sites, and 8 subjects had only transient substitutions that were not detected at the last time point on Tenvira.
g. Of the 11 HEPSERA-experienced subjects with treatment-emergent amino acid substitutions, 2 subjects had substitutions at conserved sites and 9 had substitutions only at polymorphic sites.
h. Of the 6 lamivudine-resistant subjects with treatment-emergent substitutions during Study 0121, 3 subjects had substitutions at conserved sites and 3 had substitutions only at polymorphic sites.
Compensated Liver Disease
Decompensated Liver Disease (N=39)d
Nucleotide-Naïve (N=417)a
HEPSERA-Experienced (N=247)b
Lamivudine- Resistant (N=136)c
Viremic at Last Time Point on Tenvira
38/417 (9%)
37/247 (15%)
9/136 (7%)
7/39 (18%)
Treatment-Emergent Amino Acid Substitutionse
18f/32 (56%)
11g/31 (35%)
6h/8 (75%)
3/5 (60%)
Cross Resistance
Cross resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.
In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to Tenvira ranging from 0.7-to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to Tenvira.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to Tenvira ranging from 0.6-to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to Tenvira ranging from 2.9-to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to Tenvira ranging from 0.9-to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating Tenvira therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 384 weeks of Tenvira treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir-and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
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References
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).
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).
EPA DSStox. "Tenofovir disoproxil: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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