Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive adult subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD.
In a clinical trial of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this trial, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.
The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.
Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].
Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naive subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naive subjects receiving VIREAD and/or EMTRIVA (Table 2).
Table 2 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
(Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks) | FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. | AZT/3TC + EFV |
|---|
| N=257 | N=254 |
|---|
| Gastrointestinal Disorder | | |
| Diarrhea | 9% | 5% |
| Nausea | 9% | 7% |
| Vomiting | 2% | 5% |
| General Disorders and Administration Site Condition | | |
| Fatigue | 9% | 8% |
| Infections and Infestations | | |
| Sinusitis | 8% | 4% |
| Upper respiratory tract infections | 8% | 5% |
| Nasopharyngitis | 5% | 3% |
| Nervous System Disorders | | |
| Headache | 6% | 5% |
| Dizziness | 8% | 7% |
| Psychiatric Disorders | | |
| Depression | 9% | 7% |
| Insomnia | 5% | 7% |
| Skin and Subcutaneous Tissue Disorders | | |
| Rash event Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. | 7% | 9% |
Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 3).
Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) | FTC + TDF + EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. | AZT/3TC + EFV |
|---|
| N=257 | N=254 |
|---|
| Any ≥ Grade 3 Laboratory Abnormality | 30% | 26% |
| Fasting Cholesterol (>240 mg/dL) | 22% | 24% |
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L) | 9% | 7% |
| Serum Amylase (>175 U/L) | 8% | 4% |
| Alkaline Phosphatase (>550 U/L) | 1% | 0% |
AST
(M: >180 U/L)
(F: >170 U/L) | 3% | 3% |
ALT
(M: >215 U/L)
(F: >170 U/L) | 2% | 3% |
| Hemoglobin (<8.0 mg/dL) | 0% | 4% |
| Hyperglycemia (>250 mg/dL) | 2% | 1% |
| Hematuria (>75 RBC/HPF) | 3% | 2% |
| Glycosuria (≥3+) | <1% | 1% |
| Neutrophils (<750/mm3) | 3% | 5% |
| Fasting Triglycerides (>750 mg/dL) | 4% | 2% |
In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis.
In addition to the laboratory abnormalities described above for Study 934, Grade 3/4 laboratory abnormalities of increased bilirubin (>2.5 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.
Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.
Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
There are, however, no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology trials single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one trial, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:
Chemical Structure (Truvada 01)
Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.
Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
Chemical Structure (Truvada 02)
Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.
TRUVADA: One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).
Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 4. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 4. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. 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. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.
Table 4 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in AdultsNC = Not calculated
| Emtricitabine | Tenofovir |
|---|
| Fasted Oral Bioavailability Median (range) (%) | 92 (83.1–106.4) | 25 (NC–45.0) |
| Plasma Terminal Elimination Half-Life (hr) | 10 (7.4–18.0) | 17 (12.0–25.7) |
| Cmax Mean (± SD) (µg/mL) | 1.8 ± 0.72 Data presented as steady state values. | 0.30 ± 0.09 |
| AUC (µg∙hr/mL) | 10.0 ± 3.12 | 2.29 ± 0.69 |
| CL/F (mL/min) | 302 ± 94 | 1043 ± 115 |
| CLrenal (mL/min) | 213 ± 89 | 243 ± 33 |
Effects of Food on Oral Absorption
TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.
Special Populations
Race
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.
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 VIREAD.
Gender
Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.
Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.
Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
Geriatric Patients
Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).
Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0–∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].
Patients with Hepatic Impairment
The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Assessment of Drug Interactions
The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.
In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 5 and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in trials conducted in healthy volunteers (see Tables 7 and 8).
Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered DrugAll interaction trials conducted in healthy volunteers.
| Coadministered Drug | Dose of Coadministered Drug (mg) | Emtricitabine Dose (mg) | N | % Change of Emtricitabine Pharmacokinetic Parameters ↑ = Increase; ↓ = Decrease; = No Effect; NA = Not Applicable (90% CI) |
|---|
| Cmax | AUC | Cmin |
|---|
| Tenofovir DF | 300 once daily × 7 days | 200 once daily × 7 days | 17 | | | ↑ 20
(↑ 12 to ↑ 29) |
| Zidovudine | 300 twice daily × 7 days | 200 once daily × 7 days | 27 | | | |
| Indinavir | 800 × 1 | 200 × 1 | 12 | | | NA |
| Famciclovir | 500 × 1 | 200 × 1 | 12 | | | NA |
| Stavudine | 40 × 1 | 200 × 1 | 6 | | | NA |
Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EmtricitabineAll interaction trials conducted in healthy volunteers.
| Coadministered Drug | Dose of Coadministered Drug (mg) | Emtricitabine Dose (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters ↑ = Increase; ↓ = Decrease; = No Effect; NA = Not Applicable (90% CI) |
|---|
| Cmax | AUC | Cmin |
|---|
| Tenofovir DF | 300 once daily × 7 days | 200 once daily × 7 days | 17 | | | |
| Zidovudine | 300 twice daily × 7 days | 200 once daily × 7 days | 27 | ↑ 17
(↑ 0 to ↑ 38) | ↑ 13
(↑ 5 to ↑ 20) | |
| Indinavir | 800 × 1 | 200 × 1 | 12 | | | NA |
| Famciclovir | 500 × 1 | 200 × 1 | 12 | | | NA |
| Stavudine | 40 × 1 | 200 × 1 | 6 | | | NA |
Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for TenofovirSubjects received VIREAD 300 mg once daily.
in the Presence of the Coadministered Drug| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Tenofovir Pharmacokinetic Parameters Increase = ↑; Decrease = ↓; No Effect = ; NC = Not Calculated
(90% CI) |
|---|
| Cmax | AUC | Cmin |
|---|
| Abacavir | 300 once | 8 | | | NC |
| Atazanavir Reyataz Prescribing Information | 400 once daily × 14 days | 33 | ↑ 14
(↑ 8 to ↑ 20) | ↑ 24
(↑ 21 to ↑ 28) | ↑ 22
(↑ 15 to ↑ 30) |
| Didanosine (enteric-coated) | 400 once | 25 | | | |
| Didanosine (buffered) | 250 or 400 once daily × 7 days | 14 | | | |
| Efavirenz | 600 once daily × 14 days | 29 | | | |
| Emtricitabine | 200 once daily × 7 days | 17 | | | |
| Entecavir | 1 mg once daily × 10 days | 28 | | | |
| Indinavir | 800 three times daily × 7 days | 13 | ↑ 14
(↓ 3 to ↑ 33) | | |
| Lamivudine | 150 twice daily × 7 days | 15 | | | |
| Lopinavir/Ritonavir | 400/100 twice daily × 14 days | 24 | | ↑ 32
(↑ 25 to ↑ 38) | ↑ 51
(↑ 37 to ↑ 66) |
| Nelfinavir | 1250 twice daily × 14 days | 29 | | | |
| Saquinavir/Ritonavir | 1000/100 twice daily × 14 days | 35 | | | ↑ 23
(↑ 16 to ↑ 30) |
| Tacrolimus | 0.05 mg/kg twice daily × 7 days | 21 | ↑ 13
(↑ 1 to ↑ 27) | | |
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters Increase = ↑; Decrease = ↓; No Effect = ; NA = Not Applicable
(90% CI) |
|---|
| Cmax | AUC | Cmin |
|---|
| Abacavir | 300 once | 8 | ↑ 12
(↓ 1 to ↑ 26) | | NA |
| Atazanavir Reyataz Prescribing Information | 400 once daily × 14 days | 34 | ↓ 21
(↓ 27 to ↓ 14) | ↓ 25
(↓ 30 to ↓ 19) | ↓ 40
(↓ 48 to ↓ 32) |
| Atazanavir | Atazanavir/Ritonavir 300/100 once daily × 42 days | 10 | ↓ 28
(↓ 50 to ↑ 5) | ↓ 25 In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
(↓ 42 to ↓ 3) | ↓ 23
(↓ 46 to ↑ 10) |
| Efavirenz | 600 once daily × 14 days | 30 | | | |
| Emtricitabine | 200 once daily × 7 days | 17 | | | ↑ 20
(↑ 12 to ↑ 29) |
| Indinavir | 800 three times daily × 7 days | 12 | ↓ 11
(↓ 30 to ↑ 12) | | |
| Entecavir | 1 mg once daily × 10 days | 28 | | ↑ 13
(↑ 11 to ↑ 15) | |
| Lamivudine | 150 twice daily × 7 days | 15 | ↓ 24
(↓ 34 to ↓ 12) | | |
| Lopinavir | Lopinavir/Ritonavir 400/100 twice daily × 14 days | 24 | | | |
| Ritonavir | | | |
| Methadone R-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD. | 40–110 once daily × 14 days Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported. | 13 | | | |
| Nelfinavir | 1250 twice daily × 14 days | 29 | | | |
| M8 metabolite | | | |
| Oral Contraceptives Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD. | Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) Once daily × 7 days | 20 | | | |
| Ribavirin | 600 once | 22 | | | NA |
| Saquinavir | Saquinavir/Ritonavir 1000/100 twice daily × 14 days | 32 | ↑ 22
(↑ 6 to ↑41) | ↑ 29 Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
(↑ 12 to ↑ 48) | ↑ 47
(↑ 23 to ↑ 76) |
| Ritonavir | | | ↑ 23
(↑ 3 to ↑ 46) |
| Tacrolimus | 0.05 mg/kg twice daily × 7 days | 21 | | | |
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating lack of clinically significant drug interactions between these agents and VIREAD.
Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate 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 disoproxil fumarate, 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. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.
Table 9 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD| Didanosine Administration with food was with a light meal (~373 kcal, 20% fat). Dose (mg)/Method of Administration | VIREAD Method of Administration | N | % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted Increase = ↑; Decrease = ↓; No Effect = |
|---|
| Cmax | AUC |
|---|
| Buffered tablets | | | |
| 400 once daily Includes 4 subjects weighing <60 kg receiving ddI 250 mg. × 7 days | Fasted 1 hour after didanosine | 14 | ↑ 28
(↑ 11 to ↑ 48) | ↑ 44
(↑ 31 to ↑ 59) |
| Enteric coated capsules | | | |
| 400 once, fasted | With food, 2 hours after didanosine | 26 | ↑ 48
(↑ 25 to ↑ 76) | ↑ 48
(↑ 31 to ↑ 67) |
| 400 once, with food | Simultaneously with didanosine | 26 | ↑ 64
(↑ 41 to ↑ 89) | ↑ 60
(↑ 44 to ↑ 79) |
| 250 once, fasted | With food, 2 hours after didanosine | 28 | ↓ 10
(↓ 22 to ↑ 3) | |
| 250 once, fasted | Simultaneously with didanosine | 28 | | ↑ 14
(0 to ↑ 31) |
| 250 once, with food | Simultaneously with didanosine | 28 | ↓ 29
(↓ 39 to ↓ 18) | ↓ 11
(↓ 23 to ↑ 2) |
Mechanism of Action
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 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.
Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate 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
Emtricitabine and Tenofovir Disoproxil Fumarate: In combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).
Tenofovir Disoproxil Fumarate: The antiviral activity 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 nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).
Resistance
Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical trial of treatment-naive subjects [Study 934, see Clinical Studies (14.1)], 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 discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subjects isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subjects isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. 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.
In treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD 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.
Cross Resistance
Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. 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.
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, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
Tenofovir Disoproxil Fumarate: 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.
Emtricitabine: In long-term oral 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/kg/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 disoproxil fumarate 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 disoproxil fumarate 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 disoproxil fumarate was negative when administered to male mice.
There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate 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.
21-752-GS-024
