Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate (efavirenz 600 mg lamivudine 300 mg tenofovir disoproxil fumarate 300 mg) Dailymed

12 Clinical Pharmacology

12.1 Mechanism of Action

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs EFV, 3TC, and TDF with antiviral activity against HIV-1 [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology: 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 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.16)].

12.3 Pharmacokinetics

The effect of food on efavirenz, lamivudine and tenofovir disoproxil fumarate has not been evaluated.

Efavirenz: In HIV-1-infected subjects, time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of ¹⁴C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 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 to 76 hours after single doses and 40 to 55 hours after multiple doses.

Lamivudine: After oral administration of 2 mg/kg of 3TC twice a day to 9 adults with HIV-1, the peak serum 3TC concentration (C_max) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C_maxincreased in proportion to oral dose over the range from 0.25 to 10 mg/kg and absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. Binding of 3TC to human plasma proteins is low (< 36%). Within 12 hours after a single oral dose of 3TC in 6 HIV-l-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. The majority of 3TC is eliminated unchanged in urine by active organic cationic secretion and the observed mean elimination half-life (t_1/2) ranged from 5 to 7 hours in most single-dose studies with serum sampling for 24 hours after dosing.

Tenofovir Disoproxil Fumarate: 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 2,287 ± 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 to 25 mcg/mL. Approximately 70 to 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.

Special Populations:

Race:

Efavirenz and Lamivudine: There are no significant or clinically relevant racial differences in EFV and 3TC pharmacokinetics.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.

Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of EFV, 3TC, and TDF.

Geriatric Patients: The pharmacokinetics of 3TC and TDF have not been studied in patients over 65 years of age.

Patients with Renal Impairment: [See Use in Specific Populations (8.6) .]

Efavirenz: The pharmacokinetics of EFV have not been studied in patients with renal impairment.

Lamivudine: The pharmacokinetics of 3TC are altered in subjects with renal impairment (Table 4).

Table 4. Pharmacokinetic Parameters (Mean ± SD) after a Single 300-mg Oral Dose of 3TC in Subjects with Varying Degrees of Renal Function

Parameter	Creatinine Clearance Criterion (Number of Subjects)
	> 60 mL/min (n = 6)	10 to 30 mL/min (n = 4)	< 10 mL/min (n = 6)
Creatinine clearance (mL/min)	111 ± 14	28 ± 8	6 ± 2
Cmax (mcg/mL)	2.6 ± 0.5	3.6 ± 0.8	5.8 ± 1.2
AUC∞ (mcg•h/mL)	11.0 ± 1.7	48.0 ± 19	157 ± 74
Cl/F (mL/min)	464 ± 76	114 ± 34	36 ± 11

Tenofovir Disoproxil Fumarate: The pharmacokinetics of TDF are altered in subjects with renal impairment [see Warnings and Precautions (5.4)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C_max, and AUC_{0- ∞} of tenofovir were increased.

Table 5. Pharmacokinetic Parameters (Mean ± SD) of Tenofovir After a Single 300-mg Oral Dose of TDF in Subjects with Varying Degrees of Renal Function

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

Patients with Hepatic Impairment:

Efavirenz: A multiple-dose study showed no significant effect on EFV pharmacokinetics in patients 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 EFV pharmacokinetics.

Lamivudine: The pharmacokinetic properties of 3TC have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of 3TC have not been established in the presence of decompensated liver disease.

Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg single dose of TDF have been studied in non-HIV infected subjects with moderate to severe (Child- Pugh B to C) hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

Assessment of Drug Interactions: [See Drug Interactions (7).]

Efavirenz: EFV 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, 2C19, and 3A4 with K_ivalues (8.5 to 17 mcM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K_ivalues 82 to 160 mcM) only at concentrations well above those achieved clinically. Coadministration of EFV with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of EFV resulting in lowered plasma concentrations.

Drug interaction studies were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of EFV on the C_max, AUC, and C_minare summarized in Table 6 (effect of EFV on other drugs) and Table 7 (effect of other drugs on EFV). For information regarding clinical recommendations see Drug Interactions (7.5) .

Table 6. Effect of Efavirenz on Coadministered Drug Plasma C_max, AUC, and C_min

↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%. a    90% CI not available. b   Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). c   Not available because of insufficient data. d    Study conducted with ATRIPLA®coadministered with HARVONI®. e   The predominant circulating nucleoside metabolite of sofosbuvir. f   Study conducted with ATRIPLA coadministered with SOVALDI®(sofosbuvir). g Study conducted with ATRIPLA coadministered with EPCLUSA®. NA = not available.
			Number of Subjects	Coadministered Drug (mean % change)
Coadministered Drug	Dose	Efavirenz Dose		C max (90% CI)	AUC (90% CI)	C min (90% CI)
Boceprevir	800 mg tid x 6 days	600 mg qd x 16 days	NA	↓ 8%(↓ 22 to ↑ 8%)	↓ 19%(11 to 25%)	↓ 44%(26 to 58%)
Simeprevir	150 mg qd x 14 days	600 mg qd x 14 days	23	↓ 51%(↓ 46 to ↓ 56%)	↓ 71%(↓ 67 to ↓ 74%)	↓ 91%(↓ 88 to ↓ 92%)
Ledipasvir/ Sofosbuvird  Ledipasvir Sofosbuvir GS-331007e	90/400 mg qd x 14 days	600 mg qd x 14 days	15	↓ 34(↓ 25 to ↓ 41)	↓ 34(↓ 25 to ↓ 41)	↓ 34(↓ 24 to ↓ 43)
				↔	↔	NA
				↔	↔	↔
Sofosbuvirf  GS-331007e	400 mg qd single dose	600 mg qd x 14 days	16	↓ 19(↓ 40 to ↑10)	↔	NA
				↓ 23(↓ 16 to ↓ 30)	↓ 16(↓ 24 to ↓ 8)	NA
Sofosbuvir/ Velpatasvirg  Sofosbuvir  GS-331007e  Velpatasvir	400/100 mg qd x 14 days	600 mg qd x 14 days	14
				↑ 38(↑14 to ↑67)	↔	NA
				↓ 14(↓ 20 to ↓ 7)	↔	↔
				↓ 47(↓ 57 to ↓ 36)	↓ 53(↓ 61 to ↓ 43)	↓ 57(↓ 64 to ↓ 48)
Azithromycin	600 mg single dose	400 mg qd x 7 days	14	↑ 22%(4 to 42%)	↔	NA
Clarithromycin14-OH metabolite	500 mg q12h x 7 days	400 mg qd x 7 days	11	↓ 26%(15 to 35%)	↓ 39%(30 to 46%)	↓ 53%(42 to 63%)
				↑ 49%(32 to 69%)	↑ 34%(18 to 53%)	↑ 26%(9 to 45%)
Fluconazole	200 mg x 7 days	400 mg qd x 7 days	10	↔	↔	↔
Itraconazole	200 mg q12h x 28 days	600 mg qd x 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 x 10 and 20 days	400 mg qd x 10and 20 days	11	↓ 45%(34 to 53%)	↓ 50%(40 to 57%)	NA
Rifabutin	300 mg qd x 14 days	600 mg qd x 14 days	9	↓ 32%(15 to 46%)	↓ 38%(28 to 47%)	↓ 45%(31 to 56%)
Voriconazole	400 mg po q12h x 1 day, then 200 mg po q12h x 8 days	400 mg qd x 9 days	NA	↓ 61%a	↓ 77%a	NA
	300 mg po q12h days 2 to 7	300 mg qd x 7 days	NA	↓ 36%b (21 to 49%)	↓ 55%b (45 to 62%)	NA
	400 mg po q12h days 2 to 7	300 mg qd x 7 days	NA	↑ 23%b (↓ 1 to ↑ 53%)	↓ 7%b (↓ 23 to ↑ 13%)	NA
Artemether/ lumefantrine	Artemether 20 mg/lumefantrine 120mg tablets (6 4- tablet doses over 3 days)	600 mg qd x 26 days	12
Artemether				↓ 21%	↓ 51%	NA
dihydroartemisinin				↓ 38%	↓ 46%	NA
lumefantrine				↔	↓ 21%	NA
Atorvastatin	10 mg qd x 4 days	600 mg qd x 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 x 4 days	600 mg qd x 15 days	13	↓ 32%(↓ 59 to ↑ 12%)	↓ 44%(26 to 57%)	↓ 19%(0 to 35%)
Simvastatin	40 mg qd x 4 days	600 mg qd x 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%)	NAc
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%)	↓ 27%(20 to 33%)	↓ 35%(24 to 44%)
Epoxide metabolite				↔	↔	↓ 13%(↓ 30 to ↑ 7%)
Cetirizine	10 mg single dose	600 mg qd x 10 days	11	↓ 24%(18 to 30%)	↔	NA
Diltiazem	240 mg x 21 days	600 mg qd x 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-monodes-methyl diltiazem				↓ 28%(7 to 44%)	↓ 37%(17 to 52%)	↓ 37%(17 to 52%)
Ethinyl estradiol/ Norgestimate	0.035 mg/0.25 mg x 14 days	600 mg qd x 14 days
Ethinyl estradiol			21	↔	↔	↔
Norelgestromine			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%)
Lorazepam	2 mg single dose	600 mg qd x 10 days	12	↑ 16%(2 to 32%)	↔	NA
Methadone	Stable maintenance 35 to 100 mg daily	600 mg qd x 14 to 21 days	11	↓ 45%(25 to 59%)	↓ 52%(33 to 66%)	NA
Bupropion	150 mg single dose (sustained-release)	600 mg qd x 14 days	13	↓ 34%(21 to 47%)	↓ 55%(48 to 62%)	NA
Hydroxy-bupropion				↑ 50%(20 to 80%)	↔	NA
Paroxetine	20 mg qd x 14 days	600 mg qd x 14 days	16	↔	↔	↔
Sertraline	50 mg qd x 14 days	600 mg qd x 14 days	13	↓ 29%(15 to 40%)	↓ 39%(27 to 50%)	↓ 46%(31 to 58%)

Table 7.  Effect of Coadministered Drug on Efavirenz Plasma C_max, AUC, and C_min

↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%.a    90% CI not available.b Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). NA = not available.
			Number of   Subjects	Efavirez (mean % change)
Coadministered Drug	Dose	Efavirenz Dose		C max (90% CI)	AUC (90% CI)	C min (90% CI)
Boceprevir	800 mg tid x 6 days	600 mg qd x 16 days	NA	↑ 11%(2 to 20%)	↑ 20%(15 to 26%)	NA
Simeprevir	150 mg qd x 14 days	600 mg qd x 14 days	23	↔	↓ 10%(5 to 15%)	↓ 13%(7 to 19%)
Azithromycin	600 mg single dose	400 mg qd x 7 days	14	↔	↔	↔
Clarithromycin	500 mg q12h x 7 days	400 mg qd x 7 days	12	↑ 11%(3 to 19%)	↔	↔
Fluconazole	200 mg x 7 days	400 mg qd x 7 days	10	↔	↑ 16%(6 to 26%)	↑ 22%(5 to 41%)
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%)	↓ 26%(15 to 36%)	↓ 32%(15 to 46%)
Voriconazole	400 mg po q12h x 1 day, then 200 mg po q12h x 8 days	400 mg qd x 9 days	NA	↑ 38%a	↑ 44%a	NA
	300 mg poq12h days 2 to 7	300 mg qd x 7 days	NA	↓ 14%b (7 to 21%)	↔b	NA
	400 mg poq12h days 2 to 7	300 mg qd x 7 days	NA	↔b	↑ 17%b (6 to 29%)	NA
Artemether/ Lumefantrine	Artemether 20 mg/lumefantrine120 mg tablets(6 4-tabletdoses over 3 days)	600 mg qd x 26 days	12	↔	↓ 17%	NA
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%)	↔	↓ 12%(↓ 25 to ↑ 3%)
Aluminum hydroxide 400 mg, magnesiumhydroxide 400 mg,plus simethicone 40 mg	30 mL single dose	400 mg single dose	17	↔	↔	NA
Carbamazepine	200 mg qd x 3days, 200 mg bid x 3 days, then 400 mg qd x 15 days	600 mg qd x 35 days	14	↓ 21%(15 to 26%)	↓ 36%(32 to 40%)	↓ 47%(41 to 53%)
Cetirizine	10 mg single dose	600 mg qd x 10 days	11	↔	↔	↔
Diltiazem	240 mg x 14 days	600 mg qd x 28 days	12	↑ 16%(6 to 26%)	↑ 11%(5 to 18%)	↑ 13%(1 to 26%)
Famotidine	40 mg single dose	400 mg single dose	17	↔	↔	NA
Paroxetine	20 mg qd x 14 days	600 mg qd x 14 days	12	↔	↔	↔
Sertraline	50 mg qd x 14 days	600 mg qd x 14 days	13	↑ 11%(6 to 16%)	↔	↔

Lamivudine: Effect of 3TC on the Pharmacokinetics of Other Agents: Based on in vitro study results, 3TC at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3.

Effect of Other Agents on the Pharmacokinetics of 3TC: 3TC is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase 3TC plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of 3TC is needed.

3TC is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of 3TC. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of 3TC.

Interferon Alfa: There was no significant pharmacokinetic interaction between 3TC and interferon alfa in a trial of 19 healthy male subjects.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of 3TC, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and 3TC (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.

Sorbitol (Excipient): 3TC and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of 3TC oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of 3TC with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC_{(0 to 24)}, 14%, 32%, and 36% in the AUC_(∞), and 28%, 52%, and 55% in the C_max  of  lamivudine, respectively.

Trimethoprim/Sulfamethoxazole: 3TC and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of 3TC and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of 3TC 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% ± 23% (mean ± SD) in 3TC AUC_∞, a decrease of 29% ± 13% in 3TC oral clearance, and a decrease of 30% ± 36% in 3TC renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with 3TC. There is no information regarding the effect on 3TC pharmacokinetics of higher doses of TMP/SMX such as those used in treating PCP.

Tenofovir Disoproxil Fumarate: At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro 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 tenofovir, the potential for CYP-mediated interactions involving TDF with other medicinal products is low.

Table 8 summarizes pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics. No clinically significant drug interactions have been observed between tenofovir and ribavirin.

Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir^a in the Presence of the Coadministered Drug

a    Subjects received tenofovir disoproxil fumarate 300 mg once daily. b    Increase = ↑; Decrease = ↓; No Effect = ↔; NC = Not Calculated c    Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate coadministered with ledipasvir/sofosbuvir. d    Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate coadministered with sofosbuvir. e    Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provide similar results. f     Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF. g    Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF. h    Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD® (elvitegravir/cobicistat/FTC/TDF), TRUVADA + atazanavir/ritonavir, or TRUVADA + darunavir/ritonavir. i     Administered as raltegravir + FTC/TDF. j     Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. k    Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Coadministered Drug	Dose of Coadministered Drug (mg)	N	% Change of Tenofovir Pharmacokinetic Parametersb (90% CI)
			C max	AUC	C min
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/ Sofosbuvirc	90/400 once daily x 14 days	15	↑  79(↑ 56 to ↑104)	↑  98(↑ 77 to ↑123)	↑ 163(↑ 132 to ↑ 197)
Sofosbuvir/ Velpatasvirh	400/100 once daily	24	↑  44(↑ 33 to ↑55)	↑  40(↑ 34 to ↑46)	↑ 84(↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasviri	400/100 once daily	30	↑  46(↑ 39 to ↑54)	↑ 40(↑ 34 to ↑45)	↑ 70(↑ 61 to ↑ 79)
Sofosbuvir/ Velpatasvir/Voxilaprevirj	400/100/100 +  Voxilaprevirk 100 once daily	29	↑ 48(↑ 36 to ↑61)	↑ 39(↑32 to ↑46)	↑47(↑ 38 to ↑ 56)
Sofosbuvird	400 single dose	16	↑ 25(↑ 8 to ↑ 45)	↔	↔
Tacrolimus	0.05 mg/kg twice daily x 7 days	21	↑ 13(↑ 1 to ↑ 27)	↔	↔

12.4 Microbiology

Mechanism of Action: Efavirenz: EFV is an NNRTI of HIV-1. EFV 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 EFV. Lamivudine: 3TC is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Intracellularly, 3TC is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. Tenofovir Disoproxil Fumarate: 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 (TDF-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV 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: The concentration of EFV inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90 to 95% (EC_{90 to 95}) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. Lamivudine: The antiviral activity of 3TC against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC₅₀ values were in the range of 3 to 15,000 nM. (1 mcM = 0.23 mcg/mL). The median EC₅₀ values of 3TC were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A to G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC₅₀ values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 mcM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of 3TC by 3.5-fold in MT-4 cells. Tenofovir Disoproxil Fumarate: The antiviral activity 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 (50% effective concentration) values for tenofovir were in the range of 0.04 mcM to 8.5 mcM. 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 mcM to 2.2 mcM) and strain-specific activity against HIV-2 (EC₅₀ values ranged from 1.6 mcM to 5.5 mcM). Please see the full prescribing information for VIREAD^® for information regarding the inhibitory activity of TDF against HBV. Resistance: Efavirenz: In cell culture, HIV-1 isolates with reduced susceptibility to EFV (> 380- fold increase in EC₉₀ value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase. Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. One or more RT substitutions at amino acid positions A98, L100, K101, K103, V106, V108, Y188, G190, P225, F227 and M230 were observed in patients failing treatment with EFV in combination with indinavir, or with 3TC plus zidovudine. The K103N substitution was the most frequently observed. Lamivudine: 3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that resistance was predominantly due to a methionine to valine or isoleucine (M184V/I) substitution in reverse transcriptase. 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- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. K65R substitutions developed in some subjects failing a tenofovir disoproxil fumarate regimen. Cross-Resistance: Efavirenz: Cross-resistance among NNRTIs has been observed. 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 clinical isolates tested in cell culture retained susceptibility to EFV. Lamivudine: Cross-resistance among NRTIs has been observed. 3TC-resistant HIV-1 isolates were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions. Tenofovir Disoproxil Fumarate: Cross-resistance among certain HIV-1 NRTIs has been observed. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected subjects treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to FTC and 3TC. 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.