Atripla Access (efavirenz 600 mg emtricitabine 200 mg tenofovir disoproxil fumarate 300 mg) Dailymed

12.1 Mechanism of Action

ATRIPLA is a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

Efavirenz: The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean C_max of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean C_max observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between EFV concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.4)].

12.3 Pharmacokinetics

ATRIPLA: One ATRIPLA tablet is bioequivalent to one Sustiva or Stocrin tablet (600 mg) plus one EMTRIVAâ„¢ capsule (200 mg) plus one VIREADâ„¢ 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 EFV 600 mg once daily, steady-state C_max was 12.9 ± 3.7 µM (mean ± SD), C_min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 µM∙hr. EFV is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of ¹⁴C-labeled EFV, 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 EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.

Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1–2 hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C_max 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 postdose was 0.09 µg/mL. The mean absolute bioavailability of FTC was 93%. Less than 4% of FTC binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. FTC 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 FTC half-life is approximately 10 hours.

Tenofovir DF: Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C_max) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C_max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng∙hr/mL, respectively. The oral bioavailability of tenofovir from TDF 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 EFV tablets with a high-fat meal increased the mean AUC and C_max of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either a high-fat meal or a light meal increased the mean AUC and C_max of tenofovir by 35% and 15%, respectively, without affecting FTC exposures [see Dosage and Administration (2.2) and Patient Counseling Information (17)].

Specific Populations

Race

Gender

Pediatric Patients

Geriatric Patients

Pharmacokinetics of EFV, FTC, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)].

Patients with Impaired Renal Function

Patients with Hepatic Impairment

Assessment of Drug Interactions

The drug interaction trials described were conducted with either ATRIPLA or the components of ATRIPLA (EFV, FTC, or TDF) as individual agents.

Efavirenz: The steady-state pharmacokinetics of EFV and tenofovir were unaffected when EFV and TDF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with EFV 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 EFV inhibited CYP isozymes 2C9 and 2C19 with K_i values (8.5–17 µM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K_i values 82–160 µM) only at concentrations well above those achieved clinically. Coadministration of EFV with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of EFV resulting in lowered plasma concentrations.

Drug interaction trials were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between EFV 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 EFV exposures. The effects of coadministration of EFV on C_max, AUC, and C_min are summarized in Table 4 (effect of other drugs on EFV) and Table 5 (effect of EFV on other drugs) [see Drug Interactions (7)].

Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for EFV in the Presence of the Coadministered Drug

				Mean % Change of EFV Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	EFV Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
Lopinavir/ ritonavir	400/100 mg q12h × 9 days	600 mg qd × 9 days	11, 12Parallel-group design; N for EFV + lopinavir/ritonavir, N for EFV alone.	↔	↓ 16(↓ 38 to ↑ 15)	↓ 16(↓ 42 to ↑ 20)
Nelfinavir	750 mg q8h × 7 days	600 mg qd × 7 days	10	↓ 12(↓ 32 to ↑ 13)95% CI	↓ 12(↓ 35 to ↑ 18)	↓ 21(↓ 53 to ↑ 33)
Ritonavir	500 mg q12h × 8 days	600 mg qd × 10 days	9	↑ 14(↑ 4 to ↑ 26)	↑ 21(↑ 10 to ↑ 34)	↑ 25(↑ 7 to ↑ 46)
Boceprevir	800 mg tid × 6 days	600 mg qd × 16 days	NA	↑ 11(↑ 2 to ↑ 20)	↑ 20(↑ 15 to ↑ 26)	NA
Rifabutin	300 mg qd × 14 days	600 mg qd × 14 days	11	↔	↔	↓ 12(↓ 24 to ↑ 1)
Rifampin	600 mg × 7 days	600 mg qd × 7 days	12	↓ 20(↓ 11 to ↓ 28)	↓ 26(↓ 15 to ↓ 36)	↓ 32(↓ 15 to ↓ 46)
Artemether/lumefantrine	Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)	600 mg qd × 26 days	12	↔	↓17	NA
Simvastatin	40 mg qd × 4 days	600 mg qd × 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 qd × 35 days	14	↓ 21(↓ 15 to ↓ 26)	↓ 36(↓ 32 to ↓ 40)	↓ 47(↓ 41 to ↓ 53)
Diltiazem	240 mg × 14 days	600 mg qd × 28 days	12	↑ 16(↑ 6 to ↑ 26)	↑ 11(↑ 5 to ↑ 18)	↑ 13(↑ 1 to ↑ 26)
Voriconazole	400 mg po q12h × 1 day then 200 mg po q12h × 8 days	400 mg qd × 9 days	NA	↑ 3890% CI not available	↑ 44	NA
	300 mg po q12h days 2–7	300 mg qd × 7 days	NA	↓ 14Relative to steady-state administration of EFV (600 mg once daily for 9 days). (↓ 7 to ↓ 21)	↔	NA
	400 mg po q12h days 2–7	300 mg qd × 7 days	NA	↔	↑ 17 (↑ 6 to ↑ 29)	NA

No effect on the pharmacokinetic parameters of EFV was observed with the following coadministered drugs: indinavir, saquinavir soft gelatin capsule, simeprevir, ledipasvir/sofosbuvir, sofosbuvir, clarithromycin, itraconazole, atorvastatin, pravastatin, or sertraline.

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EFV

				Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	EFV Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
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	↑ 14Compared with atazanavir 400 mg qd alone. (↓ 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 EFV)	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 qd × 10 days	20
	After morning dose			↔Comparator dose of indinavir was 800 mg q8h × 10 days.	↓ 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 qd × 9 days	11, 7Parallel-group design; N for EFV + lopinavir/ritonavir, N for lopinavir/ritonavir alone.	↔Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent EFV.	↓ 19 (↓ 36 to ↑ 3)	↓ 39 (↓ 3 to ↓ 62)
Nelfinavir	750 mg q8h × 7 days	600 mg qd × 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 qd × 10 days	11
	After AM dose			↑ 24(↑ 12 to ↑ 38)	↑ 18(↑ 6 to ↑ 33)	↑ 42(↑ 9 to ↑ 86)95% CI
	After PM dose			↔	↔	↑ 24(↑ 3 to ↑ 50)
Saquinavir SGCSoft Gelatin Capsule	1200 mg q8h × 10 days	600 mg qd × 10 days	12	↓ 50(↓ 28 to ↓ 66)	↓ 62(↓ 45 to ↓ 74)	↓ 56(↓ 16 to ↓ 77)
Maraviroc	100 mg bid	600 mg qd	12	↓ 51(↓ 37 to ↓ 62)	↓ 45(↓ 38 to ↓ 51)	↓ 45(↓ 28 to ↓ 57)
Raltegravir	400 mg single dose	600 mg qd	9	↓ 36(↓ 2 to ↓ 59)	↓ 36(↓ 20 to ↓ 48)	↓ 21(↓ 51 to ↑ 28)
Boceprevir	800 mg tid × 6 days	600 mg qd × 16 days	NA	↓ 8 (↓ 22 to ↑ 8)	↓ 19 (↓ 11 to ↓ 25)	↓ 44 (↓ 26 to ↓ 58)
Simeprevir	150 mg qd × 14 days	600 mg qd × 14 days	23	↓ 51(↓ 46 to ↓ 56)	↓ 71(↓ 67 to ↓ 74)	↓ 91(↓ 88 to ↓ 92)
Ledipasvir/sofosbuvirStudy conducted with ATRIPLA coadministered with HARVONI.	90/400 mg qd × 14 days	600 mg qd × 14 days
Ledipasvir			15	↓ 34(↓ 25 to ↓ 41)	↓ 34(↓ 25 to ↓ 41)	↓ 34(↓ 24 to ↓ 43)
Sofosbuvir				↔	↔	NA
GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.				↔	↔	↔
SofosbuvirStudy conducted with ATRIPLA coadministered with SOVALDI™ (sofosbuvir).	400 mg qd single dose	600 mg qd ×14 days	16	↓ 19(↓ 40 to ↑ 10)	↔	NA
GS-331007				↓ 23(↓ 16 to ↓ 30)	↓ 16(↓ 24 to ↓ 8)	NA
Sofosbuvir/velpatasvirStudy conducted with ATRIPLA coadministered with EPCLUSA.	400/100 mg qd × 14 days	600 mg qd × 14 days	14
Sofosbuvir				↑ 38(↑ 14 to ↑ 67)	↔	NA
GS-331007				↓ 14(↓ 20 to ↓ 7)	↔	↔
Velpatasvir				↓ 47(↓ 57 to ↓ 36)	↓ 53(↓ 61 to ↓ 43)	↓ 57(↓ 64 to ↓ 48)
Clarithromycin	500 mg q12h × 7 days	400 mg qd × 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 qd × 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)
Posaconazole	400 mg (oral suspension) bid × 10 and 20 days	400 mg qd × 10 and 20 days	11	↓ 45(↓ 34 to ↓ 53)	↓ 50(↓ 40 to ↓ 57)	NA
Rifabutin	300 mg qd × 14 days	600 mg qd × 14 days	9	↓ 32(↓ 15 to ↓ 46)	↓ 38(↓ 28 to ↓ 47)	↓ 45(↓ 31 to ↓ 56)
Artemether/lumefantrine	Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)	600 mg qd × 26 days	12
Artemether				↓ 21↓ 38	↓ 51	NA
dihydroartemisinin				↔	↓ 46	NA
lumefantrine					↓21	NA
Atorvastatin	10 mg qd × 4 days	600 mg qd × 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 qd × 15 days	13	↓ 32(↓ 59 to ↑ 12)	↓ 44(↓ 26 to ↓ 57)	↓ 19(↓ 0 to ↓ 35)
Simvastatin	40 mg qd × 4 days	600 mg qd × 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)	NANot available because of insufficient data.
Carbamazepine	200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 29 days	600 mg qd × 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 qd × 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 qd × 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 qd × 14–21 days	11	↓ 45(↓ 25 to ↓ 59)	↓ 52(↓ 33 to ↓ 66)	NA
Bupropion	150 mg single dose (sustained-release)	600 mg qd × 14 days	13	↓ 34(↓21 to ↓47)	↓ 55(↓48 to ↓62)	NA
Hydroxybupropion				↑ 50(↑ 20 to ↑ 80)	↔	NA
Sertraline	50 mg qd × 14 days	600 mg qd × 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 qd × 9 days	NA	↓ 6190% CI not available	↓ 77	NA
	300 mg po q12h days 2–7	300 mg qd × 7 days	NA	↓ 36Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). (↓ 21 to ↓ 49)	↓ 55 (↓ 45 to ↓ 62)	NA
	400 mg po q12h days 2–7	300 mg qd × 7 days	NA	↑ 23 (↓ 1 to ↑ 53)	↓ 7 (↓ 23 to ↑ 13)	NA

Emtricitabine and Tenofovir DF: The steady-state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF 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 FTC and tenofovir with other medicinal products is low.

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

No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, sofosbuvir/velpatasvir, stavudine, TDF, and zidovudine. Similarly, no clinically significant drug interactions have been observed between TDF and abacavir, EFV, FTC, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, 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 TDF.

The effects of coadministered drugs on the C_max, AUC, and C_min of tenofovir are shown in Table 6. The effects of coadministration of TDF on C_max, AUC, and C_min of coadministered drugs are shown in Table 7.

Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered DrugAll interaction trials conducted in healthy volunteers. ^, Subjects received TDF 300 mg once daily.

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
			Cmax	AUC	Cmin
AtazanavirReyataz Prescribing Information.	400 once daily × 14 days	33	↑ 14(↑ 8 to ↑ 20)	↑ 24(↑ 21 to ↑ 28)	↑ 22(↑ 15 to ↑ 30)
Atazanavir/ritonavir	300/100 once daily	12	↑ 34(↑ 20 to ↑ 51)	↑ 37(↑ 30 to ↑ 45)	↑ 29(↑ 21 to ↑ 36)
Darunavir/ritonavirPrezista Prescribing Information.	300/100 twice daily	12	↑ 24(↑ 8 to ↑ 42)	↑ 22(↑ 10 to ↑ 35)	↑ 37(↑ 19 to ↑ 57)
DidanosineSubjects received didanosine buffered tablets.	250 or 400 once daily × 7 days	14	↔	↔	↔
Ledipasvir/sofosbuvir	90/400 once daily	15	↑ 79(↑ 56 to ↑ 104)	↑ 98(↑ 77 to ↑ 123)	↑ 163(↑ 132 to ↑ 197)
Lopinavir/ritonavir	400/100 twice daily × 14 days	24	↔	↑ 32(↑ 25 to ↑ 38)	↑ 51(↑ 37 to ↑ 66)
Sofosbuvir	400 once daily	16	↑ 25(↑ 8 to ↑ 45)	↔	↔
Sofosbuvir/velpatasvir	400/100 once daily	15	↑ 77(↑ 53 to ↑ 104)	↑ 81(↑ 68 to ↑ 94)	↑ 121(↑ 100 to ↑ 143)
Tipranavir/ritonavirAptivus Prescribing Information.	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)

Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDFAll interaction trials conducted in healthy volunteers. ^, Subjects received TDF 300 mg once daily.

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
			Cmax	AUC	Cmin
AtazanavirReyataz Prescribing Information.	400 once daily × 14 days	34	↓ 21(↓ 27 to ↓ 14)	↓ 25(↓ 30 to ↓ 19)	↓ 40(↓ 48 to ↓ 32)
	Atazanavir/ritonavir 300/100 once daily × 42 days	10	↓ 28(↓ 50 to ↑ 5)	↓ 25In HIV-infected patients, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. (↓ 42 to ↓ 3)	↓ 23 (↓ 46 to ↑ 10)
DarunavirPrezista Prescribing Information.	Darunavir/ritonavir 300/100 once daily	12	↑ 16(↓ 6 to ↑ 42)	↑ 21(↓ 5 to ↑ 54)	↑ 24(↓ 10 to ↑ 69)
DidanosineVidex EC Prescribing Information. Subjects received didanosine enteric-coated capsules.	250 once, simultaneously with TDF and a light meal373 kcal, 8.2 g fat.	33	↓ 20Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. (↓ 32 to ↓ 7)	↔	NA
Lopinavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔
Ritonavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔
TipranavirAptivus Prescribing Information.	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)

12.4 Microbiology

Mechanism of Action

Efavirenz: EFV is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by EFV.

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form FTC 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 polymerases α, β, ε, and mitochondrial DNA polymerase γ.

Tenofovir DF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. 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.

Antiviral Activity

Efavirenz, Emtricitabine, and Tenofovir DF: In combination studies evaluating the antiviral activity in cell culture of FTC and EFV together, EFV and tenofovir together, and FTC and tenofovir together, additive to synergistic antiviral effects were observed.

Efavirenz: The concentration of EFV inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC_90–95) 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 FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC₅₀) values for FTC were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of FTC with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, EFV, 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 DF: 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, EFV, 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 1.6–5.5 µM).

Resistance

EFV, FTC, and TDF: HIV-1 isolates with reduced susceptibility to the combination of FTC 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 addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir.

In a clinical trial of treatment-naïve subjects [Study 934, see Clinical Studies (14)] 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 EFV, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to EFV occurred in 13/19 analyzed subjects in the FTC + TDF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to FTC and lamivudine, was observed in 2/19 analyzed subject isolates in the FTC + TDF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

In a clinical trial of treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects receiving TDF 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 TDF 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 HIV-1 RT gene resulting in the K65R amino acid substitution.

Efavirenz: Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. The most frequently observed amino acid substitution in clinical trials with EFV 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 EFV 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 EFV (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 FTC was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

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

Cross Resistance

Efavirenz, Emtricitabine, and Tenofovir DF: 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 FTC and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or FTC, 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 EFV 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 EFV in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to EFV.

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

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