Atripla (Page 7 of 12)

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%. In vitro binding of emtricitabine to human plasma proteins is <4% and 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%. In vitro binding of tenofovir to human plasma proteins is <0.7% and 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 (2) and Patient Counseling Information (17.3)].

Special Populations

Race

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.

Gender

Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Efavirenz, emtricitabine, and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric and Geriatric Patients

Pharmacokinetic studies of tenofovir DF have not been performed in pediatric subjects (<18 years). Efavirenz has not been studied in pediatric subjects below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. ATRIPLA is not recommended for pediatric administration. Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years) [See Use in Specific Populations (8)].

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 <50 mL/min, Cmax and AUC0– of emtricitabine and tenofovir were increased [See Warnings and Precautions (5.7)].

Patients with Hepatic Impairment

Efavirenz: The pharmacokinetics of efavirenz have not been adequately studied in subjects with hepatic impairment [See Warnings and Precautions (5.10) and Use in Specific Populations (8.6)].

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 studies described were conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents; no drug interaction studies 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 studies 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. 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 studies 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 (7).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Efavirenz in the Presence of the Coadministered Drug
Mean % Change of Efavirenz Pharmacokinetic Parameters * (90% CI)
Coadministered Drug Dose of Coadministered Drug (mg) Efavirenz Dose (mg) N Cmax AUC Cmin
NA = not available
*
Increase = ↑; Decrease = ↓; No Effect = ↔
Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone.
95% CI
§
Soft Gelatin Capsule
90% CI not available
#
Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).
Indinavir 800 mg q8h × 14 days 200 mg × 14 days 11
Lopinavir/ ritonavir 400/100 mg q12h × 9 days 600 mg × 9 days 11, 12 ↓ 16 (↓ 38 to ↑ 15) ↓ 16 (↓ 42 to ↑ 20)
Nelfinavir 750 mg q8h × 7 days 600 mg × 7 days 10 ↓ 12 (↓ 32 to ↑ 13) ↓ 12 (↓ 35 to ↑ 18) ↓ 21 (↓ 53 to ↑ 33)
Ritonavir 500 mg q12h × 8 days 600 mg × 10 days 9 ↑ 14 (↑ 4 to ↑ 26) ↑ 21 (↑ 10 to ↑ 34) ↑ 25 (↑ 7 to ↑ 46)
Saquinavir SGC § 1200 mg q8h × 10 days 600 mg × 10 days 13 ↓ 13 (↓ 5 to ↓ 20) ↓ 12 (↓ 4 to ↓ 19) ↓ 14 (↓ 2 to ↓ 24)
Clarithromycin 500 mg q12h × 7 days 400 mg × 7 days 12 ↑ 11 (↑ 3 to ↑ 19)
Itraconazole 200 mg q12h × 14 days 600 mg × 28 days 16
Rifabutin 300 mg qd × 14 days 600 mg × 14 days 11 ↓ 12 (↓ 24 to ↑ 1)
Rifampin 600 mg × 7 days 600 mg × 7 days 12 ↓ 20 (↓ 11 to ↓ 28) ↓ 26 (↓ 15 to ↓ 36) ↓ 32 (↓ 15 to ↓ 46)
Atorvastatin 10 mg qd × 4 days 600 mg × 15 days 14
Pravastatin 40 mg qd × 4 days 600 mg × 15 days 11
Simvastatin 40 mg qd × 4 days 600 mg × 15 days 14 ↓ 12 (↓ 28 to ↑ 8) ↓ 12 (↓ 25 to ↑ 3)
Carbamazepine 200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 15 days 600 mg × 35 days 14 ↓ 21 (↓ 15 to ↓ 26) ↓ 36 (↓ 32 to ↓ 40) ↓ 47 (↓ 41 to ↓ 53)
Diltiazem 240 mg × 14 days 600 mg × 28 days 12 ↑ 16 (↑ 6 to ↑ 26) ↑ 11 (↑ 5 to ↑ 18) ↑ 13 (↑ 1 to ↑ 26)
Sertraline 50 mg qd × 14 days 600 mg × 14 days 13 ↑ 11 (↑ 6 to ↑ 16)
Voriconazole 400 mg po q12h × 1 day then 200 mg po q12h × 8 days 400 mg × 9 days NA ↑ 38 ↑ 44 NA
300 mg po q12h days 2–7 300 mg × 7 days NA ↓ 14# (↓ 7 to ↓ 21) # NA
400 mg po q12h days 2–7 300 mg × 7 days NA # ↑ 17# (↑ 6 to ↑ 29) NA
Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Efavirenz
Mean % Change of Coadministered Drug Pharmacokinetic Parameters * (90% CI)
Coadministered Drug Dose of Coadministered Drug (mg) Efavirenz Dose (mg) N Cmax AUC Cmin
NA = not available
*
Increase = ↑; Decrease = ↓; No Effect = ↔
Compared with atazanavir 400 mg qd alone.
Comparator dose of indinavir was 800 mg q8h × 10 days.
§
Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone.
Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent efavirenz.
#
95% CI
Þ
Soft Gelatin Capsule
ß
Not available because of insufficient data.
à
90% CI not available
è
Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
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) ↓ 74 (↓ 68 to ↓ 78) ↓ 93 (↓ 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 ↑ 14 (↓ 17 to ↑ 58) ↑ 39 (↑ 2 to ↑ 88) ↑ 48 (↑ 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 d 11–24 (pm) 14 ↑ 17(↑ 8 to ↑ 27) ↓ 42(↓ 31 to ↓ 51)
Indinavir 1000 mg q8h × 10 days 600 mg × 10 days 20
After morning dose

↓ 33 (↓ 26 to ↓ 39) ↓ 39 (↓ 24 to ↓ 51)
After afternoon dose

↓ 37 (↓ 26 to ↓ 46) ↓ 52 (↓ 47 to ↓ 57)
After evening dose ↓ 29 (↓ 11 to ↓ 43) ↓ 46 (↓ 37 to ↓ 54) ↓ 57 (↓ 50 to ↓ 63)
Lopinavir/ ritonavir 400/100 mg q12h × 9 days 600 mg × 9 days 11, 7§

↓ 19 (↓ 36 to ↑ 3) ↓ 39 (↓ 3 to ↓ 62)
Nelfinavir 750 mg q8h × 7 days 600 mg × 7 days 10 ↑ 21 (↑ 10 to ↑ 33) ↑ 20 (↑ 8 to ↑ 34)
Metabolite AG-1402 ↓ 40 (↓ 30 to ↓ 48) ↓ 37 (↓ 25 to ↓ 48) ↓ 43 (↓ 21 to ↓ 59)
Ritonavir 500 mg q12h × 8 days 600 mg × 10 days 11
After AM dose ↑ 24 (↑ 12 to ↑ 38) ↑ 18 (↑ 6 to ↑ 33) ↑ 42 (↑ 9 to ↑ 86)#
After PM dose ↑ 24 (↑ 3 to ↑ 50)#
Saquinavir SGC Þ 1200 mg q8h × 10 days 600 mg × 10 days 12 ↓ 50 (↓ 28 to ↓ 66) ↓ 62 (↓ 45 to ↓ 74) ↓ 56 (↓ 16 to ↓ 77)#
Clarithromycin 500 mg q12h × 7 days 400 mg × 7 days 11 ↓ 26 (↓ 15 to ↓ 35) ↓ 39 (↓ 30 to ↓ 46) ↓ 53 (↓ 42 to ↓ 63)
14-OH metabolite ↑ 49 (↑ 32 to ↑ 69) ↑ 34 (↑ 18 to ↑ 53) ↑ 26 (↑ 9 to ↑ 45)
Itraconazole 200 mg q12h × 28 days 600 mg ×14 days 18 ↓ 37 (↓ 20 to ↓ 51) ↓ 39 (↓ 21 to ↓ 53) ↓ 44 (↓ 27 to ↓ 58)
Hydroxy-itraconazole ↓ 35 (↓ 12 to ↓ 52) ↓ 37 (↓ 14 to ↓ 55) ↓ 43 (↓ 18 to ↓ 60)
Rifabutin 300 mg qd × 14 days 600 mg × 14 days 9 ↓ 32 (↓ 15 to ↓ 46) ↓ 38 (↓ 28 to ↓ 47) ↓ 45 (↓ 31 to ↓ 56)
Atorvastatin 10 mg qd × 4 days 600 mg × 15 days 14 ↓ 14 (↓ 1 to ↓ 26) ↓ 43 (↓ 34 to ↓ 50) ↓ 69 (↓ 49 to ↓ 81)
Total active (including metabolites) ↓ 15 (↓ 2 to ↓ 26) ↓ 32 (↓ 21 to ↓ 41) ↓ 48 (↓ 23 to ↓ 64)
Pravastatin 40 mg qd × 4 days 600 mg × 15 days 13 ↓ 32 (↓ 59 to ↑ 12) ↓ 44 (↓ 26 to ↓ 57) ↓ 19 (↓ 0 to ↓ 35)
Simvastatin 40 mg qd × 4 days 600 mg × 15 days 14 ↓ 72 (↓ 63 to ↓ 79) ↓ 68 (↓ 62 to ↓ 73) ↓ 45 (↓ 20 to ↓ 62)
Total active (including metabolites) ↓ 68 (↓ 55 to ↓ 78) ↓ 60 (↓ 52 to ↓ 68) NA ß
Carbamazepine 200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 29 days 600 mg × 14 days 12 ↓ 20 (↓ 15 to ↓ 24) ↓ 27 (↓ 20 to ↓ 33) ↓ 35 (↓ 24 to ↓ 44)
Epoxide metabolite ↓ 13 (↓ 30 to ↑ 7)
Diltiazem 240 mg × 21 days 600 mg × 14 days 13 ↓ 60 (↓ 50 to ↓ 68) ↓ 69 (↓ 55 to ↓ 79) ↓ 63 (↓ 44 to ↓ 75)
Desacetyl diltiazem ↓ 64 (↓ 57 to ↓ 69) ↓ 75 (↓ 59 to ↓ 84) ↓ 62 (↓ 44 to ↓ 75)
N-monodesmethyl diltiazem ↓ 28 (↓ 7 to ↓ 44) ↓ 37 (↓ 17 to ↓ 52) ↓ 37 (↓ 17 to ↓ 52)
Ethinyl estradiol/ Norgestimate 0.035 mg/0.25 mg × 14 days 600 mg × 14 days
Ethinyl estradiol 21
Norelgestromin 21 ↓ 46(↓39 to ↓ 52) ↓ 64(↓ 62 to ↓ 67) ↓ 82(↓ 79 to ↓ 85)
Levonorgestrel 6 ↓ 80(↓77 to ↓ 83) ↓ 83(↓79 to ↓ 87) ↓ 86(↓80 to ↓ 90)
Methadone Stable maintenance 35–100 mg daily 600 mg × 14–21 days 11 ↓ 45 (↓ 25 to ↓ 59) ↓ 52 (↓ 33 to ↓ 66) NA
Sertraline 50 mg qd × 14 days 600 mg × 14 days 13 ↓ 29 (↓ 15 to ↓ 40) ↓ 39 (↓ 27 to ↓ 50) ↓ 46 (↓ 31 to ↓ 58)
Voriconazole 400 mg po q12h × 1 day then 200 mg po q12h × 8 days 400 mg × 9 days NA ↓ 61à ↓ 77à NA
300 mg po q12h days 2–7 300 mg × 7 days NA ↓ 36è (↓ 21 to ↓ 49) ↓ 55è (↓ 45 to ↓ 62) NA
400 mg po q12h days 2–7 300 mg × 7 days NA ↑ 23è (↓ 1 to ↑ 53 ↓ 7è (↓ 23 to ↑ 13) NA

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