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For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA and VIREAD prescribing information.
Mechanism of Action
ATRIPLA is a fixed-dose combination of antiviral drugs efavirenz, emtricitabine and tenofovir disoproxil fumarate.
ATRIPLA: One ATRIPLA tablet is bioequivalent to one SUSTIVA tablet (600 mg) plus one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).
Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM·hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14– 34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.
Emtricitabine: Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 μg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg/mL. The mean absolute bioavailability of emtricitabine was 93%. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02-200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate: Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70-80% 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 with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Effects of Food on Oral Absorption
ATRIPLA has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].
Efavirenz: The pharmacokinetics of efavirenz in HIV-1 infected subjects appear to be similar among the racial groups studied.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.
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 tenofovir DF.
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Efavirenz, emtricitabine, and tenofovir pharmacokinetics are similar in male and female subjects.
ATRIPLA should only be administered to pediatric patients 12 years of age and weighing greater than or equal to 40 kg (greater than or equal to 88 lb).
Efavirenz: In an open-label trial in NRTI-experienced pediatric subjects (mean age 8 years, range 3-16), the pharmacokinetics of efavirenz in pediatric subjects were similar to the pharmacokinetics in adults who received a 600 mg daily dose of efavirenz. In 48 pediatric subjects, receiving the equivalent of a 600 mg dose of efavirenz, mean (± SD) steady-state Cmax was 14.2 ± 5.8 μM, steady-state Cmin was 5.6 ± 4.1 μM, and AUC was 218 ± 104 μM•hr.
Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.
Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [See Use In Specific Populations].
Patients with Impaired Renal Function
Efavirenz: The pharmacokinetics of efavirenz have not been studied in subjects with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min, Cmax and AUC0-∞ of emtricitabine and tenofovir were increased [See WARNINGS AND PRECAUTIONS].
Patients with Hepatic Impairment
Efavirenz: A multiple-dose trial showed no significant effect on efavirenz pharmacokinetics in subjects with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. [See WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF 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.
Assessment of Drug Interactions
The drug interaction trials described were conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents; no drug interaction trials have been conducted using ATRIPLA.
Efavirenz: The steady-state pharmacokinetics of efavirenz and tenofovir were unaffected when efavirenz and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with efavirenz and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways.
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values (8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82–160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Drug interaction trials were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between efavirenz and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on efavirenz exposures. The effects of coadministration of efavirenz on Cmax, AUC, and Cmin are summarized in Table 5 (effect of other drugs on efavirenz) and Table 6 (effect of efavirenz on other drugs). For information regarding clinical recommendations see DRUG INTERACTIONS.
Table 5 : Drug Interactions: Changes in
Pharmacokinetic Parameters for Efavirenzin the Presence of the Coadministered
|Coadministered Drug||Dose of Coadministered Drug (mg)||Efavirenz Dose (mg)||N||Mean % Change of Efavirenz Pharmacokinetic Parametersa 90% CI)|
|Indinavir||800 mg q8h x 14 days||200 mg qd x 14 days||11||↔||↔||↔|
|Lopinavir/ ritonavir||400/100 mg q12h x 9 days||600 mg qd x 9 days||11, 12b||↔||↓ 16
(↓ 38 to ↑15)
(↓ 42 to ↑20)
|Nelfinavir||750 mg q8h x 7 days||600 mg qd x 7 days||10||↓12
(↓ 32 to ↑ 13)c
(↓ 53 to ↑33)
|Ritonavir||500 mg q12h x 8 days||600 mg qd x 10 days||9||↑14
(↑4 to ↑26)
(↑10 to ↑34)
(↑7 to ↑46)c
|Saquinavir SGCd||1200 mg q8h x 10 days||600 mg qd x 10 days||13||↓13
(↓5 to ↓20)
(↓ 4 to ↓19)
(↓2 to ↓24)c
|Boceprevir||800 mg tid x 6 days||600 mg qd x 16 days||NA||↑11
(↑2 to ↑20)
|↑20(↑15 to ↑ 26)||NA|
|Telaprevir||750 mg q8h x 10 days||600 mg qd x 20 days||21||↓16
(↓2 to ↓13)
(↓ 6 to ↑2)
|Telaprevir, coadministered with tenofovir disoproxil fumarate
|1125 mg q8h x 7 days||600 mg efavirenz/300 mg TDF qd x 7 days||15||↓24
(↓15 to ↓32)
(↓10 to ↓26)
(↓19 to ↑ 1)
|1500 mg q12h x 7 days||600 mg efavirenz/300 mg TDF qd x 7 days||16||↓20
(↓14 to ↓ 26)
(↓9 to ↓21)
|Clarithromycin||500 mg q12h x 7 days||400 mg qd x 7 days||12||↑11
(↑3 to ↑19)
|Itraconazole||200 mg q12h x 14 days||600 mg qd x 28 days||16||↔||↔||↔|
|Rifabutin||300 mg qd x 14 days||600 mg qd x 14 days||11||↔||↔||↓12
(↓ 24 to ↑ 1)
|Rifampin||600 mg x 7 days||600 mg qd x 7 days||12||↓20
(↓11 to ↓ 28)
(↓15 to ↓36)
(↓ 15 to ↓46)
|Atorvastatin||10 mg qd x 4 days||600 mg qd x 15 days||14||↔||↔||↔|
|Pravastatin||40 mg qd x 4 days||600 mg qd x 15 days||11||↔||↔||↔|
|Simvastatin||40 mg qd x 4 days||600 mg qd x 15 days||14||↓ 12
(↓28 to ↑8)
(↓25 to ↑3)
|Carbamazepine||200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days||600 mg qd x 35 days||14||↓21
(↓15 to ↓26)
(↓ 32 to ↓40)
(↓ 41 to ↓53)
|Diltiazem||240 mg x 14 days||600 mg qd x 28 days||12||↑ 16
(↑6 to ↑26)
(↑ 5 to ↑18)
(↑ 1 to ↑26)
|Sertraline||50 mg qd x 14 days||600 mg qd x 14 days||13||↑11
(↑6 to ↑16)
|Voriconazole||400 mg po q12h x 1 day then 200 mg po q12h x 8 days||400 mg qd x 9 days||NA||↑38e||↑44e||NA|
|300 mg po q12h days 2-7||300 mg qd x 7 days||NA||↓14f (↓7 to ↓21)||↔f||NA|
|400 mg po q12h days 2-7||300 mg qd x 7 days||NA||↔f||↑17f
(↑ 6 to ↑29)
|NA = not available
a Increase = ↑; Decrease =↓; No Effect = ↔
b Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone.
c 95% CI
d Soft Gelatin Capsule
e 90% CI not available
f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).
Table 6 : Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence
|Coadministered Drug||Dose of Coadministered Drug (mg)||Efavirenz Dose (mg)||N||Mean % Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI)|
|Atazanavir||400 mg qd with a light meal d 1-20||600 mg qd with a light meal d 7-20||27||↓ 59
(↓ 49 to↓67)
(↓68 to ↓78)
(↓90 to ↓95)
|400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal||600 mg qd 2 h after atazanavir and ritonavir d 7-20||13||↑14b (↓ 17 to ↑ 58)||↑ 39b
(↑ 2 to ↑88)
(↑24 to ↑76)
|300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz)||600 mg qd with a light snack d11-24 (pm)||14||↑17
(↑ 8 to ↑27)
(↓31 to ↓51)
|Indinavir||1000 mg q8h x 10 days||600 mg qd x 10 days||20|
|After morning dose||↔c||↓33c (↓26 to ↓39)||↓39c
(↓ 24 to↓51)
|After afternoon dose||↔c||↓37c
(↓26 to ↓46)
(↓47 to ↓57)
|After evening dose||↓29c
(↓37 to ↓ 54)
(↓50 to ↓63)
|Lopinavir/ ritonavir||400/100 mg q12h x 9 days||600 mg qd x 9 days||11, 7d||↔e||↓19e
(↓ 36 to ↑ 3)
|↓ 39e (↓3 to ↓62)|
|Nelfinavir||750 mg q8h x 7 days||600 mg qd x 7 days||10||↑ 21
(↑10 to ↑ 33)
(↑8 to ↑ 34)
|Metabolite AG-1402||↓ 40
(↓ 30 to ↓48)
(↓25 to ↓48)
(↓21 to ↓ 59)
|Ritonavir||500 mg q12h x 8 days||600 mg qd x 10 days||11|
|After AM dose||↑ 24
(↑ 12 to ↑ 38)
(↑ 6 to ↑ 33)
(↑ 9 to ↑ 86)f
|After PM dose||↔||↔||↑24
(↑3 to ↑ 50)f
|Saquinavir SGCg||1200 mg q8h x 10 days||600 mg qd x 10 days||12||↓ 50
(↓ 28 to ↓66)
(↓45 to ↓74)
(↓16 to ↓77)f
|Maraviroc||100 mg bid||600 mg qd||12||↓51
(↓37 to ↓62)
(↓38 to ↓51)
(↓28 to ↓57)
|Raltegravir||400 mg single dose||600 mg qd||9||↓ 36
(↓2 to ↓59)
(↓20 to ↓48)
(↓51 to ↑28)
|Boceprevir||800 mg tid x 6 days||600 mg qd x 16 days||NA||↓ 8
(↓ 22 to ↓ 8)
(↓11 to ↓25)
(↓26 to ↓ 58)
|Telaprevir||750 mg q8h x 10 days||600 mg qd x 20 days||21||↓9
(↓18 to ↑2)
(↓16 to ↓35)
(↓35 to ↓56)
|500 mg q12h x 7 days||400 mg qd x 7 days||11||↓26
(↓15 to ↓35)
(↓ 30 to ↓46)
(↓42 to ↓63)
(↑32 to ↑ 69)
(↑18 to ↑53)
(↑9 to ↑45)
|Itraconazole||200 mg q12h x 28 days||600 mg qd x 14 days||18||↓ 37
(↓20 to ↓51)
(↓21 to ↓53)
(↓27 to↓ 58)
(↓ 12 to ↓52)
(↓14 to↓ 55)
(↓18 to ↓ 60)
|Posaconazole||400 mg (oral suspension) bid x 10 and 20 days||400 mg qd x 10 and 20 days||11||↓45
(↓ 34 to↓53)
(↓40 to ↓57)
|Rifabutin||300 mg qd x 14 days||600 mg qd x 14 days||9||↓32
(↓15 to ↓46)
(↓28 to ↓47)
(↓31 to ↓ 56)
|Atorvastatin||10 mg qd x 4 days||600 mg qd x 15 days||14||↓14
(↓34 to ↓50)
(↓49 to ↓81)
(↓ 2 to↓26)
(↓21 to ↓41)
(↓23 to↓ 64)
|Pravastatin||40 mg qd x 4 days||600 mg qd x 15 days||13||↓32
(↓ 59 to ↑12)
(↓26 to ↓57)
(↓0 to ↓35)
|Simvastatin||40 mg qd x 4 days||600 mg qd x 15 days||14||↓72
(↓ 63 to ↓79)
(↓62 to ↓73)
(↓20 to ↓62)
(↓55 to ↓78)
(↓52 to ↓68)
|Carbamazepine||200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days||600 mg qd x 14 days||12||↓ 20
(↓15 to ↓24)
(↓20 to ↓33)
(↓ 24 to ↓ 44)
(↓30 to ↓ 7)
|Diltiazem||240 mg x 21 days||600 mg qd x 14 days||13||↓60
(↓50 to ↓68)
(↓55 to ↓79)
(↓44 to ↓75)
(↓ 57 to ↓69)
(↓59 to ↓84)
(↓44 to ↓ 75)
(↓7 to ↓44)
(↓17 to ↓52)
(↓17 to ↓ 52)
|Ethinyl estradiol/ Norgestimate||0.035 mg/0.25 mg x 14 days||600 mg qd x 14 days|
(↓39 to ↓52)
(↓62 to ↓67)
(↓79 to ↓ 85)
(↓80 to ↓90)
|Methadone||Stable maintenance 35-100 mg daily||600 mg qd x 14-21 days||11||↓45
(↓ 25 to ↓59)
(↓ 33 to ↓66)
|Bupropion||150 mg single dose
|600 mg qd x 14 days||13||↓ 34
(↓21 to ↓47)
(↓48 to ↓62)
(↑ 20 to ↑ 80)
|Sertraline||50 mg qd x 14 days||600 mg qd x 14 days||13||↓29
(↓ 15 to ↓40)
(↓31 to ↓ 58)
|400 mg po q12h x 1 day then 200 mg po q12h x 8 days||400 mg qd x 9 days||NA||↓61h||↓77h||NA|
|Voriconazole||300 mg po q12h days 2-7||300 mg qd x 7 days||NA||↓ 36i
(↓ 21 to ↓ 49)
(↓ 45 to ↓ 62)
|400 mg po q12h days 2-7||300 mg qd x 7 days||NA||↑ 23i
(↓ 1 to ↑53
(↓ 23 to ↑13)
|NA = not available
a Increase = ↑; Decrease =↓; No Effect = ↔
b Compared with atazanavir 400 mg qd alone.
c Comparator dose of indinavir was 800 mg q8h × 10 days.
d Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone.
e Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent efavirenz.
f 95% CI
g Soft Gelatin Capsule.
h. 90% CI not available
i. Relative to steady-state administration of voriconazole
(400 mg for 1 day, then 200 mg po q12h for 2 days).
j Not available because of insufficient data.
Emtricitabine and Tenofovir Disoproxil Fumarate: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir or tacrolimus in trials conducted in healthy volunteers.
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.
The effects of coadministered drugs on the Cmax, AUC, and Cmin of tenofovir are shown in Table 7. The effects of coadministration of tenofovir DF on Cmax, AUC, and Cmin of coadministered drugs are shown in Table 8 and Table 9.
Table 7: Drug Interactions: Changes in Pharmacokinetic
Parameters for Tenofovirin the Presence of the Coadministered Druga,b
|Coadministered Drug||Dose of Coadministered Drug (mg)||N||Mean % Change of Tenofovir Pharmacokinetic Parametersc (90% CI)|
|Atazanavird||400 once daily x 14 days||33||↑ 14
(↑ 8 to ↑20)
(↑21 to ↑28)
(↑15 to ↑ 30)
|Didanosinee||250 or 400 once daily x 7 days||14||↔||↔||↔|
|Lopinavir/ ritonavir||400/100 twice daily x 14 days||24||↔||↑32
(↑25 to ↑38)
(↑37 to ↑66)
|a All interaction trials conducted in healthy
b Subjects received tenofovir DF 300 mg once daily.
c Increase = ↑; Decrease =↓; No Effect = ↔
d Reyataz Prescribing Information.
e Subjects received didanosine buffered tablets.
Table 8 : Drug Interactions: Changes in
Pharmacokinetic Parameters forCoadministered Drug in the Presence of Tenofovir
|Coadministered Drug||Dose of Coadministered Drug (mg)||N||Mean % Change of Coadministered Drug Pharmacokinetic Parametersc (90% CI)|
|Atazanavird||400 once daily x 14 days||34||↓21
(↓ 48 to ↓ 32)
|Atazanavir/ritonavir 300/100 once daily x 42 days||10||↓28
(↓50 to↑ 5)
(↓42 to ↓3)
(↓ 46 to ↑10)
|Didanosinef||250 once, simultaneously with tenofovir DF and a light mealg||33||↓20h
(↓32 to↓ 7)
|Lopinavir||Lopinavir/ritonavir 400/100 twice daily x 14 days||24||↔||↔||↔|
|Ritonavir||Lopinavir/ritonavir 400/100 twice daily x 14 days||24||↔||↔||↔|
|a All interaction trials conducted in healthy
b Subjects received tenofovir DF 300 mg once daily.
c Increase = ↑; Decrease =↓; No Effect = ↔
d Reyataz Prescribing Information.
e In HIV-infected patients, addition of tenofovir 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.
f Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules.
g 373 kcal, 8.2 g fat.
h Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.
Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir DF with didanosine enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown [for didanosine dosing adjustment recommendations see DRUG INTERACTIONS, Table 4].
Mechanism of Action
Efavirenz: Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.
Tenofovir Disoproxil Fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate 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. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.
Efavirenz: The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC90-95) ranged from 1.7-25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2.
Emtricitabine: The antiviral activity in cell culture of emtricitabine 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 emtricitabine were in the range of 0.0013–0.64 μM (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM).
Tenofovir Disoproxil Fumarate: The antiviral activity in cell culture 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 0.04–8.5 μM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were 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 0.5–2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical trial of treatment-naive subjects [Study 934, see Clinical Studies] 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 discontinuations. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 analyzed subjects in the emtricitabine + tenofovir DF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/19 analyzed subject isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
In a clinical trial of treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed greater than 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV1 RT gene resulting in the K65R amino acid substitution.
Efavirenz: Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most frequently observed amino acid substitution in clinical trials with efavirenz is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in subjects failing treatment with efavirenz in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).
HIV-1 isolates with reduced susceptibility to efavirenz (greater than 380-fold increase in EC90 value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT.
Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical trials. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine 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 2–4 fold reduction in susceptibility to tenofovir.
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Cross-resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, 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.
Efavirenz: Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine-and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to efavirenz.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.
Tenofovir Disoproxil Fumarate: The K65R substitution selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. 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 VIREAD. 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.
Animal Toxicology and/or Pharmacology
Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4-to 13-fold greater than those in humans given the recommended dose.
Tenofovir Disoproxil Fumarate: Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species administered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
Clinical Study 934 supports the use of ATRIPLA tablets in antiretroviral treatment-naive HIV-1 infected patients. Additional data in support of the use of ATRIPLA in treatment-naive patients can be found in the prescribing information for VIREAD.
Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to ATRIPLA.
In antiretroviral treatment-experienced patients, the use of ATRIPLA tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing [See CLINICAL PHARMACOLOGY].
Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF fixed-dose combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm³ (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count ( < or ≥ 200 cells/mm³) and 41% had CD4+ cell counts < 200 cells/mm³. Fifty-one percent (51%) of subjects had baseline viral loads > 100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline (N=487) are presented in Table 10.
Table 10 : Outcomes of
Randomized Treatment at Weeks 48 and 144 (Study 934)
|Outcomes||At Week 48||At Week 144|
|FTC + TDF +EFV
|FTC + TDF +EFV
|Change in antiretroviral regimen||1%||1%||1%||1%|
|Discontinued due to adverse event||4%||9%||5%||12%|
|Discontinued for other reasonsd||10%||14%||20%||22%|
|a Subjects who were responders at Week 48 or
Week 96 (HIV-1 RNA < 400 copies/mL) but did not consent to continue trial
after Week 48 or Week 96 were excluded from analysis.
b Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Weeks 48 and 144.
c Includes confirmed viral rebound and failure to achieve confirmed HIV-1 RNA < 400 copies/mL through Weeks 48 and 144.
d Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA < 400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA < 400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm³ in the emtricitabine + tenofovir DF group and 158 cells/mm³ in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm³ at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Study 073 was a 48-week open-label, randomized clinical trial in subjects with stable, virologic suppression on combination antiretroviral therapy consisting of at least two nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a protease inhibitor (with or without ritonavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
To be enrolled, subjects were to have HIV-1 RNA < 200 copies/mL for at least 12 weeks on their current regimen prior to trial entry with no known HIV-1 substitutions conferring resistance to the components of ATRIPLA and no history of virologic failure.
The trial compared the efficacy of switching to ATRIPLA or staying on the baseline antiretroviral regimen (SBR). Subjects were randomized in a 2:1 ratio to switch to ATRIPLA (N=203) or stay on SBR (N=97). Subjects had a mean age of 43 years (range 22 to 73 years), 88% were male, 68% were white, 29% were black or African-American, and 3% were of other races. At baseline, median CD4+ cell count was 516 cells/mm³ and 96% had HIV-1 RNA < 50 copies/mL. The median time since onset of antiretroviral therapy was 3 years and 88% of subjects were receiving their first antiretroviral regimen at trial enrollment.
At Week 48, 89% and 87% of subjects who switched to ATRIPLA maintained HIV RNA < 200 copies/mL and < 50 copies/mL, respectively, compared to 88% and 85% who remained on SBR; this difference was not statistically significant. No changes in CD4+ cell counts from baseline to Week 48 were observed in either treatment arm.
Last reviewed on RxList: 4/29/2013
This monograph has been modified to include the generic and brand name in many instances.
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