CLINICAL PHARMACOLOGY
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. [See Clinical Pharmacology].
Pharmacokinetics
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 patients time-to-peak plasma concentrations were approximately 3—5 hours and steady-state plasma concentrations were reached in 6—10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 ΅M (mean ± SD), Cmin was 5.6 ± 3.2 ΅M, and AUC was 184 ± 73 ΅M β 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 P450 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 ΅g/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 ΅gβhr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 ΅g/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 ΅g/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 patients 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 ngβhr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted patients 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 ΅g/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 Counseling Information].
Special Populations
Race
Efavirenz: The pharmacokinetics of efavirenz in patients 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 patients.
Pediatric and Geriatric Patients
Pharmacokinetic studies of tenofovir DF have not been performed in pediatric patients (<18 years). Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric patients 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 patients 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 patients with renal impairment. In patients with creatinine clearance <50 mL/min, Cmax and AUC0β β of emtricitabine and tenofovir were increased [See Warnings and Precautions].
Patients with Hepatic Impairment
Efavirenz: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment [See Warnings and Precautions and Use in Specific Populations].
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in patients 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 patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients.
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 P450 isozymes 2C9, 2C19, and 3A4 with Ki values (8.5—17 ΅M) 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 ΅M) 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
ParametersIncrease = β; Decrease = β; No Effect = β (90% CI) |
| Coadministered Drug | Dose of Coadministered Drug (mg) | Efavirenz Dose (mg) | N | Cmax | AUC | Cmin |
| NA = not available |
| Indinavir | 800 mg q8h 14 days | 200 mg 14 days | 11 | β | β | β |
Lopinavir/
ritonavir | 400/100 mg q12h 9 days | 600 mg 9 days | 11, 12Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone. | β | β 16
(β 38 to β 15) | β 16
(β 42 to β 20) |
| Nelfinavir | 750 mg q8h 7 days | 600 mg 7 days | 10 | β 12
(β 32 to — 13)
| β 12
(β 35 to β 18) | β 21
(β 53 to β 33) |
| Ritonavir | 500 mg q12h 8 days | 600 mg 10 days | 9 | β 14
(β 4 to β 26) | β 21
(β 10 to β 34) | β 25
(β 7 to — 46) |
| Saquinavir SGCSoft Gelatin Capsule | 1200 mg q8h 10 days | 600 mg 10 days | 13 | β 13
(β 5 to — 20) | β 12
(β 4 to — 19) | β 14
(β 2 to β 24) |
| Clarithromycin | 500 mg q12h 7 days | 400 mg 7 days | 12 | β 11
(β 3 to β 19) | β | β |
| Itraconazole | 200 mg q12h 14 days | 600 mg 28 days | 16 | β | β | β |
| Rifabutin | 300 mg qd 14 days | 600 mg 14 days | 11 | β | β | β 12
(β 24 to — 1) |
| Rifampin | 600 mg 7 days | 600 mg 7 days | 12 | β 20
(β 11 to β 28) | β 26
(β 15 to β 36) | β 32
(β 15 to β 46) |
| Atorvastatin | 10 mg qd 4 days | 600 mg 15 days | 14 | β | β | β |
| Pravastatin | 40 mg qd 4 days | 600 mg 15 days | 11 | β | β | β |
| Simvastatin | 40 mg qd 4 days | 600 mg 15 days | 14 | β 12
(β 28 to — 8) | β | β 12
(β 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 | β 21
(β 15 to — 26) | β 36
(β 32 to β 40) | β 47
(β 41 to β 53) |
| Diltiazem | 240 mg 14 days | 600 mg 28 days | 12 | β 16
(β 6 to — 26) | β 11
(β 5 to — 18) | β 13
(β 1 to — 26) |
| Ethinyl estradiol | 50 ΅g single dose | 400 mg 10 days | 13 | β | β | β |
| Sertraline | 50 mg qd 14 days | 600 mg 14 days | 13 | β 11
(β 6 to — 16) | β | β |
| Voriconazole | 400 mg po q12h 1 day then 200 mg po q12h 8 days | 400 mg 9 days | NA | β 38
| β 44 | NA |
| 300 mg po q12h days 2—7 | 300 mg 7 days | NA | β 14
(β 7 to — 21) | β | NA |
| 400 mg po q12h days 2—7 | 300 mg 7 days | NA | β | β 17
(β 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
ParametersIncrease = β; Decrease = β; No Effect = β (90% CI) |
| Coadministered Drug | Dose of Coadministered Drug (mg) | Efavirenz 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 | β 59
(β 49 to — 67) | β 74
(β 68 to — 78) | β 93
(β 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 | β 14
(β 17 to β 58) | β 39
(β 2 to β 88) | β 48
(β 24 to — 76) |
| Indinavir | 1000 mg q8h 10 days | 600 mg 10 days | 20 | | | |
| | After morning dose | |
β
| β 33
(β 26 to — 39) | β 39
(β 24 to — 51) |
| After afternoon dose | |
β
| β 37
(β 26 to — 46) | β 52
(β 47 to — 57) |
| | After evening dose | | β 29
(β 11 to — 43) | β 46
(β 37 to — 54) | β 57
(β 50 to — 63) |
Lopinavir/
ritonavir | 400/100 mg q12h 9 days | 600 mg 9 days | 11, 7Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone. |
β
| β 19
(β 36 to — 3) | β 39
(β 3 to β 62) |
| Nelfinavir | 750 mg q8h 7 days | 600 mg 7 days | 10 | β 21
(β 10 to — 33) | β 20
(β 8 to β 34) | β |
Metabolite
AG-1402 | | | | β 40
(β 30 to — 48) | β 37
(β 25 to — 48) | β 43
(β 21 to — 59) |
| Ritonavir | 500 mg q12h 8 days | 600 mg 10 days | 11 | | | |
| | After AM dose | | β 24
(β 12 to β 38) | β 18
(β 6 to β 33) | β 42
(β 9 to — 86) |
| | After PM dose | | β | β | β 24
(β 3 to — 50)
|
Saquinavir
SGC
| 1200 mg q8h 10 days | 600 mg 10 days | 12 | β 50
(β 28 to β 66) | β 62
(β 45 to β 74) | β 56
(β 16 to β 77) |
| Clarithromycin | 500 mg q12h 7 days | 400 mg 7 days | 11 | β 26
(β 15 to β 35) | β 39
(β 30 to — 46) | β 53
(β 42 to — 63) |
| 14-OH metabolite | | | | β 49
(β 32 to β 69) | β 34
(β 18 to — 53) | β 26
(β 9 to — 45) |
| Itraconazole | 200 mg q12h 28 days | 600 mg 14 days | 18 | β 37
(β 20 to β 51) | β 39
(β 21 to — 53) | β 44
(β 27 to β 58) |
| Hydroxy-itraconazole | β 35
(β 12 to β 52) | β 37
(β 14 to β 55) | β 43
(β 18 to β 60) |
| Rifabutin | 300 mg qd 14 days | 600 mg 14 days | 9 | β 32
(β 15 to — 46) | β 38
(β 28 to — 47) | β 45
(β 31 to — 56) |
| Atorvastatin | 10 mg qd 4 days | 600 mg 15 days | 14 | β 14
(β 1 to — 26) | β 43
(β 34 to — 50) | β 69
(β 49 to — 81) |
| Total active (including metabolites) | | | | β 15
(β 2 to — 26) | β 32
(β 21 to — 41) | β 48
(β 23 to — 64) |
| Pravastatin | 40 mg qd 4 days | 600 mg 15 days | 13 | β 32
(β 59 to — 12) | β 44
(β 26 to — 57) | β 19
(β 0 to — 35) |
| Simvastatin | 40 mg qd 4 days | 600 mg 15 days | 14 | β 72
(β 63 to — 79) | β 68
(β 62 to β 73) | β 45
(β 20 to — 62) |
| Total active (including metabolites) | | | | β 68
(β 55 to — 78) | β 60
(β 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 14 days | 12 | β 20
(β 15 to — 24) | β 27
(β 20 to — 33) | β 35
(β 24 to — 44) |
| Epoxide metabolite | | | | β | β | β 13
(β 30 to — 7) |
| Diltiazem | 240 mg 21 days | 600 mg 14 days | 13 | β 60
(β 50 to — 68) | β 69
(β 55 to — 79) | β 63
(β 44 to β 75) |
| Desacetyl diltiazem | β 64
(β 57 to — 69) | β 75
(β 59 to — 84) | β 62
(β 44 to — 75) |
| N-monodesmethyl diltiazem | β 28
(β 7 to — 44) | β 37
(β 17 to — 52) | β 37
(β 17 to — 52) |
| Ethinyl estradiol | 50 ΅g single dose | 400 mg 10 days | 13 | β | β 37
(β 25 to β 51) | NA |
| Methadone | Stable maintenance 35—100 mg daily | 600 mg
14—21 days | 11 | β 45
(β 25 to — 59) | β 52
(β 33 to — 66) | NA |
| Sertraline | 50 mg qd 14 days | 600 mg 14 days | 13 | β 29
(β 15 to β 40) | β 39
(β 27 to — 50) | β 46
(β 31 to — 58) |
| Voriconazole | 400 mg po q12h 1 day then 200 mg po q12h 8 days | 400 mg 9 days
| NA | β 61
| β 77 | NA |
| 300 mg po q12h days 2—7 | 300 mg 7 days | NA | β 36
(β 21 to β 49) | β 55
(β 45 to — 62) | NA |
| 400 mg po q12h days 2—7 | 300 mg 7 days | NA | β 23
(β 1 to β 53 | β 7
(β 23 to — 13) | NA |
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, adefovir dipivoxil, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir in studies 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 studies, 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 Tenofovir in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. , Patients received tenofovir DF 300 mg once daily. | Coadministered Drug | Dose of Coadministered Drug (mg) | N | Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = β; Decrease = β; No Effect = β
(90% CI) |
| Cmax | AUC | Cmin |
| AtazanavirReyataz Prescribing Information | 400 once daily
14 days | 33 | β 14
(β 8 to — 20) | β 24
(β 21 to — 28) | β 22
(β 15 to — 30) |
| Didanosine (enteric-coated) | 400 once | 25 | β | β | β |
| Didanosine (buffered) | 250 or 400 once daily 7 days | 14 | β | β | β |
| Lopinavir/ ritonavir | 400/100 twice daily 14 days | 24 | β | β 32
(β 25 to — 38) | β 51
(β 37 to — 66) |
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil FumarateAll interaction studies conducted in healthy volunteers. , Patients received tenofovir DF 300 mg once daily. | Coadministered Drug | Dose of Coadministered Drug (mg) | N | Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = β; Decrease = β; No Effect = β
(90% CI) |
| Cmax | AUC | Cmin |
| AtazanavirReyataz Prescribing Information | 400 once daily
14 days | 34 | β 21
(β 27 to — 14) | β 25
(β 30 to — 19) | β 40
(β 48 to — 32) |
| | Atazanavir/ritonavir
300/100 once daily
42 days | 10 | β 28
(β 50 to — 5) | β 25
(β 42 to — 3) | β 23
(β 46 to — 10) |
| Lopinavir | Lopinavir/ritonavir 400/100 twice daily 14 days | 24 | β | β | β |
| Ritonavir | Lopinavir/ritonavir 400/100 twice daily 14 days | 24 | β | β | β |
Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir DF on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir DF with didanosine buffered tablets or 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.
Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir Disoproxil FumarateAll interaction studies conducted in healthy volunteers. ,
| Didanosine Dose (mg)/Method of Administration
| Tenofovir DF Method of Administration , | N | Mean % Change (90% CI) vs. Didanosine 400 mg Alone, FastedIncrease = β; Decrease = β; No Effect = β |
| Cmax | AUC |
| Buffered tablets | | | |
| 400 once dailyIncludes 4 subjects weighing <60 kg receiving ddI 250 mg. 7 days | Fasted 1 hour after didanosine | 14 | β 28
(β 11 to — 48) | β 44
(β 31 to — 59) |
| Enteric coated capsules | | | |
| 400 once, fasted | With food, 2 hr after didanosine | 26 | β 48
(β 25 to — 76) | β 48
(β 31 to — 67) |
| 400 once, with food | Simultaneously with didanosine | 26 | β 64
(β 41 to — 89) | β 60
(β 44 to — 79) |
| 250 once, fasted | With food, 2 hr after didanosine | 28 | β 10
(β 22 to — 3) | β |
| 250 once, fasted | Simultaneously with didanosine | 28 | β | β 14
(0 to — 31) |
| 250 once, with food | Simultaneously with didanosine | 28 | β 29
(β 39 to — 18) | β 11
(β 23 to — 2) |
Microbiology
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 alpha, beta, Ξ³, and Ξ΄ 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 alpha, beta, Ξ΅, and mitochondrial DNA polymerase Ξ³.
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 alpha, beta, and mitochondrial DNA polymerase Ξ³.
Antiviral Activity
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 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 ΅M (0.0003—0.158 ΅g/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 ΅M) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007—1.5 ΅M).
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 ΅M. 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 ΅M) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 ΅M to 5.5 ΅M).
Resistance
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 studies. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical study of treatment-naive patients [Study 934, see Clinical Studies] resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients with >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 patients in the emtricitabine + tenofovir DF group and in 21/29 analyzed patients 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 patient isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed patient isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no patients developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
In a clinical study of treatment-naive patients, isolates from 8/47 (17%) analyzed patients 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 patients, 14/304 (5%) of tenofovir DF treated patients with virologic failure through Week 96 showed >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 efavirenz have been obtained. The most frequently observed amino acid substitution in clinical studies 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 patients 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 (>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 studies. 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.
Cross Resistance
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 patients (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. Multinucleoside resistant HIV-1 with a T69S double insertion substitution in the RT showed reduced susceptibility to tenofovir.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.
Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.
Emtricitabine: In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 times the human systemic exposure at the therapeutic dose).
Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.
Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.
There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
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.
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