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:Vidara disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Vidara disoproxil fumarate requires initial diester hydrolysis for conversion to Vidara and subsequent phosphorylations by cellular enzymes to form Vidara diphosphate, an obligate chain terminator. Vidara 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. Vidara 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 Vidara 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 Vidara were in the range of 0.04-8.5 micromolar. In drug combination studies of Vidara 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. Vidara 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 Vidara against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for Vidara ranged from 0.14-1.5 micromolar, with 50% cytotoxicity concentration (CC50) values >100 micromolar. In cell culture combination, antiviral activity studies of Vidara with the nucleoside, anti-HBV reverse transcriptase inhibitors emtricitabine, entecavir, lamivudine and telbivudine, no antagonistic activity was observed.
Pharmacokinetics:Absorption: Vidara is a water soluble diester prodrug of the active ingredient Vidara. The oral bioavailability of Vidara from Tenovir in fasted subjects is approximately 25%. Following oral administration of a single-dose Vidara 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 Vidara are dose proportional over a Vidara dose range of 75-600 mg and are not affected by repeated dosing.
Distribution:In vitro binding of Vidara to human plasma or serum proteins is <0.7% and 7.2%, respectively, over the Vidara 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 Vidara 1 mg/kg and 3 mg/kg.
Metabolism and Elimination:In vitro studies indicate that neither Vidara disoproxil nor Vidara are substrates of cytochrome (CYP) enzymes. Following IV administration of Vidara, approximately 70-80% of the dose is recovered in the urine as unchanged Vidara within 72 hrs of dosing. Following single dose, oral administration of Vidara, the terminal elimination half-life of Vidara 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. Vidara 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 Vidara following a high-fat meal (~700-1000 kCal containing fat 40-50%) increases the oral bioavailability, with an increased Vidara AUC(0-∞); of approximately 40% and an increased Cmax of approximately 14%. However, administration of Vidara with a light meal did not have a significant effect on the pharmacokinetics of Vidara when compared to fasted administration of the drug. Food delays the time to Vidara Cmax by approximately 1 hr. Cmax and AUC of Vidara are 0.33±0.12 mcg/mL and 3.32±1.37 mcg·hr/mL following multiple doses of Vidara 300 mg once daily in the fed state, when meal content was not controlled.
How should I take Vidara?
Take darunavir, cobicistat, emtricitabine, and Vidara 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 Vidara 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 Vidara alafenamide without checking first with your doctor. When your supply of darunavir, cobicistat, emtricitabine, and Vidara alafenamide is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of darunavir, cobicistat, emtricitabine, and Vidara alafenamide.
Take darunavir, cobicistat, emtricitabine, and Vidara 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 Vidara 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 Vidara 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 Vidara alafenamide.
Children—Use and dose must be determined by your doctor.
Missed Dose
If you miss a dose of darunavir, cobicistat, emtricitabine, and Vidara 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.
Vidara 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.
Vidara 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
Vidara DF is an antiviral drug.
Pharmacokinetics
The pharmacokinetics of Vidara DF have been evaluated in healthy volunteers and HIV-1 infected individuals. Vidara pharmacokinetics are similar between these populations.
Absorption
Vidara Disoproxil Fumarate is a water soluble diester prodrug of the active ingredient Vidara. The oral bioavailability of Vidara from Vidara Disoproxil Fumarate in fasted subjects is approximately 25%. Following oral administration of a single dose of Vidara Disoproxil Fumarate 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 Vidara are dose proportional over a Vidara Disoproxil Fumarate dose range of 75 to 600 mg and are not affected by repeated dosing.
Distribution
In vitro binding of Vidara to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the Vidara 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 Vidara 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither Vidara disoproxil nor Vidara are substrates of CYP enzymes.
Following IV administration of Vidara, approximately 70 to 80% of the dose is recovered in the urine as unchanged Vidara within 72 hours of dosing. Following single dose, oral administration of Vidara Disoproxil Fumarate, the terminal elimination half-life of Vidara is approximately 17 hours. After multiple oral doses of Vidara Disoproxil Fumarate 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Vidara 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 Vidara Disoproxil Fumarate 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 Vidara AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Vidara Disoproxil Fumarate with a light meal did not have a significant effect on the pharmacokinetics of Vidara when compared to fasted administration of the drug. Food delays the time to Vidara Cmax by approximately 1 hour. Cmax and AUC of Vidara are 0.33 ± 0.12 mcg/mL and 3.32 ± 1.37 mcg•hr/mL following multiple doses of Vidara Disoproxil Fumarate 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: Vidara pharmacokinetics are similar in male and female subjects.
Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of Vidara were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 10). Vidara exposure achieved in these pediatric subjects receiving oral once daily doses of Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 300 mg.
Table 10 Mean (± SD) Vidara 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
Vidara exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of Vidara Disoproxil Fumarate 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 Vidara 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 Vidara were increased (Table 11). It is recommended that the dosing interval for Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate.
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
Vidara is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Vidara Disoproxil Fumarate, a four-hour hemodialysis session removed approximately 10% of the administered Vidara dose.
Patients with Hepatic Impairment: The pharmacokinetics of Vidara following a 300 mg single dose of Vidara Disoproxil Fumarate have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in Vidara pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in Vidara Disoproxil Fumarate dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, Vidara 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 Vidara, the potential for CYP-mediated interactions involving Vidara with other medicinal products is low.
Vidara Disoproxil Fumarate 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 Vidara pharmacokinetics and effects of Vidara Disoproxil Fumarate on the pharmacokinetics of coadministered drug. Coadministration of Vidara Disoproxil Fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of Vidara Disoproxil Fumarate with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with Vidara Disoproxil Fumarate, 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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/Vidara DF.
g. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/Vidara DF.
h Study conducted with ATRIPLA (efavirenz/emtricitabine/Vidara DF) coadministered with HARVONI.
i. Study conducted with COMPLERA (emtricitabine/rilpivirine/Vidara DF) coadministered with HARVONI.
j. Study conducted with TRUVADA (emtricitabine/Vidara 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/Vidara DF.
m. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/Vidara DF.
n. Study conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir).
o. Study conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/Vidara DF) coadministered with EPCLUSA.
p. Study conducted with COMPLERA coadministered with EPCLUSA.
q. Administered as raltegravir + emtricitabine/Vidara DF.
r. Aptivus Prescribing Information.
Coadministered Drug
Dose of Coadministered Drug (mg)
N
% Change of Vidara 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 Vidara Disoproxil Fumarate: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.
Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Vidara Disoproxil Fumarate
a. Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable
b. Reyataz Prescribing Information.
c. In HIV-infected subjects, addition of Vidara 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 Vidara 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 Vidara Disoproxil Fumarate 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
Vidara DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Vidara DF requires initial diester hydrolysis for conversion to Vidara and subsequent phosphorylations by cellular enzymes to form Vidara diphosphate, an obligate chain terminator. Vidara 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. Vidara 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 Vidara 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 Vidara were in the range of 0.04 mcM to 8.5 mcM. In drug combination studies, Vidara 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). Vidara 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 Vidara 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 Vidara. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by Vidara and results in low-level reduced susceptibility to Vidara.
In Study 903 of treatment-naïve subjects (Vidara Disoproxil Fumarate + 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 Vidara Disoproxil Fumarate arm and in 2/49 (4%) of analyzed patient isolates in the stavudine arm. Of the 8 subjects whose virus developed K65R in the Vidara Disoproxil Fumarate arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the Vidara Disoproxil Fumarate arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to Vidara Disoproxil Fumarate were not identified in this trial.
In Study 934 of treatment-naïve subjects (Vidara Disoproxil Fumarate + 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 Vidara Disoproxil Fumarate + 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 Vidara 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 Vidara.
In Studies 902 and 907 conducted in treatment-experienced subjects (Vidara Disoproxil Fumarate + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the Vidara Disoproxil Fumarate -treated subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility to Vidara. 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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. Vidara Disoproxil Fumarate -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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Vidara Disoproxil Fumarate. 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate and response to Vidara Disoproxil Fumarate therapy. Table 14 summarizes the HIV-1 RNA response by baseline Vidara Disoproxil Fumarate susceptibility.
Table 14 HIV-1 RNA Response at Week 24 by Baseline Vidara Disoproxil Fumarate Susceptibility (Intent-To-Treat)a
a. Vidara 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.
The antiviral activity of Vidara against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for Vidara 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 Vidara 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate (genotypic and phenotypic analyses).
Table 15 Amino Acid Substitutions in Viremic Subjects across HBV Trials of Vidara Disoproxil Fumarate
a. Nucleotide-naïve subjects from Studies 0102 (N=246) and 0103 (N=171) receiving up to 384 weeks of treatment with Vidara Disoproxil Fumarate.
b. HEPSERA-experienced subjects from Studies 0102/0103 (N=195) and 0106 (N=52) receiving up to 336 weeks of treatment with Vidara Disoproxil Fumarate after switching to Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate after switching to Vidara Disoproxil Fumarate from lamivudine.
d. Subjects with decompensated liver disease from Study 0108 (N=39) receiving up to 48 weeks of treatment with Vidara Disoproxil Fumarate.
e. Denominator includes those subjects who were viremic at last time point on Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate.
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 Vidara Disoproxil Fumarate
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 Vidara 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 Vidara.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to Vidara 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 Vidara ranging from 2.9-to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to Vidara ranging from 0.9-to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating Vidara Disoproxil Fumarate 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 Vidara Disoproxil Fumarate 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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