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Viread (Tenofovir Disoproxil Fumarate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

VIREAD is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

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:

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.

VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Y–30—10671–A, which contains FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [See Clinical Pharmacology].

Pharmacokinetics

The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Absorption

VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 ΅g/mL and 2.29 ± 0.69 ΅g βˆ™ hr/mL, respectively.

The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.

Distribution

In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 ΅g/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism and Elimination

In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.

Following IV administration of tenofovir, approximately 70—80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Effects of Food on Oral Absorption

Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0– ∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 ΅g/mL and 3.32 ± 1.37 ΅g βˆ™ hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations

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

Gender: Tenofovir pharmacokinetics are similar in male and female patients.

Pediatric and Geriatric Patients: Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years).

Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in patients with renal impairment [See Warnings and Precautions]. In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0– ∞ of tenofovir were increased (Table 9). It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis [See Dosage and Administration].

Table 9 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir300 mg, single dose of VIREAD in Patients with Varying Degrees of Renal Function
Baseline Creatinine Clearance (mL/min) >80
(N=3)
50—80
(N=10)
30—49
(N=8)
12—29
(N=11)
Cmax (΅g/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC0– ∞ (΅gβˆ™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

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.

Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD 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. No change in VIREAD dosing is required in patients with hepatic impairment.

Assessment of Drug Interactions

At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: 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 tenofovir with other medicinal products is low [See Clinical Pharmacology].

VIREAD has been evaluated in healthy volunteers in combination with abacavir, atazanavir, didanosine, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus. Tables 10 and 11 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for TenofovirPatients 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
AtazanavirReyataz 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)

Following multiple dosing to HIV- and HBV-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 studies, indicating lack of clinically significant drug interactions between these agents and VIREAD.

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIREAD
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 1 400 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 2
(↓ 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)
Entecavir 1 mg once daily
— 10 days
28
↑ 13
(↑ 11 to — 15)
Indinavir 800 three times daily — 7 days 12 ↓ 11
(↓ 30 to — 12)
Lamivudine 150 twice daily
— 7 days
15 ↓ 24
(↓ 34 to — 12)
Lopinavir Lopinavir/Ritonavir 400/100 twice daily — 14 days 24
Ritonavir
MethadoneR-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD. 40—110 once daily
— 14 daysIndividual 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 ContraceptivesEthinyl 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 3
(↑ 12 to — 48)
↑ 47
(↑ 23 to — 76)
Ritonavir
↑ 23
(↑ 3 to — 46)
Tacrolimus 0.05 mg/kg twice
daily — 7 days
21

1 Reyataz Prescribing Information
2 In HIV-infected patients, 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.
3 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.

Table 12 summarizes the drug interaction between VIREAD and didanosine. Coadministration of VIREAD and didanosine should be undertaken with caution [See Drug Interactions]. When administered with multiple doses of VIREAD, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

Table 12 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD
Didanosine Dose (mg)/ Method of Administration VIREAD Method of AdministrationAdministration with food was with a light meal (~373 kcal, 20% fat). N % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted

Increase = ↑; Decrease = ↓; No Effect =

Cmax AUC
Buffered tablets
400 once dailyIncludes 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)

Microbiology

Mechanism of Action

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, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV polymerase 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.

Activity against HIV

Antiviral Activity

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 ΅M to 8.5 ΅M. 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 ΅M to 2.2 ΅M) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 ΅M to 5.5 ΅M).

Resistance

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

In Study 903 of treatment-naive patients (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See Clinical Studies], genotypic analyses of isolates from patients with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 patients whose virus developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to VIREAD were not identified in this study.

In Study 934 of treatment-naive patients (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz) [See Clinical Studies], genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed patient isolates in the VIREAD + EMTRIVA group and in 10/29 analyzed patient isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no patients have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Cross Resistance

Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with this mutation also show 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 reverse transcriptase 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 reverse transcriptase showed reduced susceptibility to tenofovir.

In Studies 902 and 907 conducted in treatment-experienced patients (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT) [See Clinical Studies], 14/304 (5%) of the VIREAD-treated patients with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced patients participating in Studies 902 and 907.

In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. These included resistance substitutions associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), the abacavir/emtricitabine/lamivudine resistance-associated substitution (M184V), and others. In addition the majority of participants evaluated had substitutions associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall study results.

Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions were observed and appeared to depend on the number of specific substitutions. VIREAD-treated patients whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy.

In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. In the presence of zidovudine resistance-associated substitutions, the M184V substitution did not affect the mean HIV-1 RNA responses to VIREAD treatment. HIV-1 RNA responses among these patients were durable through Week 48.

Studies 902 and 907 Phenotypic Analyses

The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-experienced patients participating in two controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 13 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 13 HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (Intent-To-Treat)Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
Baseline VIREAD SusceptibilityFold change in susceptibility from wild-type. Change in HIV-1 RNAAverage HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL. (N)
<1 -0.74 (35)
>1 and ≤3 -0.56 (49)
>3 and ≤4 -0.3 (7)
>4 -0.12 (9)

Activity against HBV

Antiviral Activity

The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 ΅M, with CC50 (50% cytotoxicity concentration) values >100 ΅M. In cell culture combination antiviral activity studies of tenofovir with the nucleoside anti-HBV reverse transcriptase inhibitors emtricitabine, entecavir, lamivudine and telbivudine, no antagonistic activity was observed.

Resistance

Out of 426 HBeAg negative and HBeAg positive patients, 39 patients had serum HBV DNA >400 copies/mL at Week 48. Genotypic data from paired baseline and on treatment isolates were available for 28 of the 39 patients. No specific amino acid substitutions occurred in these subjects' isolates at sufficient frequency to establish an association with tenofovir resistance.

Cross Resistance

Cross-resistance has been observed among HBV reverse transcriptase inhibitors.

In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7 to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.

HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6 to 6.9-fold that of wild type virus. An HBV strain expressing rtL180M, rtT184G, rtS202I and rtM204V together had a 6.9-fold reduction in susceptibility to tenofovir.

HBV strains expressing the adefovir-associated resistance substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9 to 10-fold that of wild type virus.

Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9 to 1.5-fold that of wild type virus.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Animal Toxicology and/or Pharmacology

Tenofovir and tenofovir disoproxil fumarate 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. 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.

CLINICAL STUDIES

Clinical Efficacy in Patients with HIV-1 Infection

Treatment-Na―ve Patients

Study 903

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naive patients. Patients had a mean age of 36 years (range 18—64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3—956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417—5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of patients had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 14.

Table 14 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)
At Week 48 At Week 144
Outcomes VIREAD+3TC
+EFV
(N=299)
d4T+3TC
+EFV
(N=301)
VIREAD+3TC
+EFV
(N=299)
d4T+3TC
+EFV
(N=301)
ResponderPatients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. 79% 82% 68% 62%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144. 6% 4% 10% 8%
  Rebound 5% 3% 8% 7%
  Never suppressed 0% 1% 0% 0%
  Added an antiretroviral agent 1% 1% 2% 1%
Death <1% 1% <1% 2%
Discontinued due to adverse event 6% 6% 8% 13%
Discontinued for other reasonsIncludes lost to follow-up, patient's withdrawal, noncompliance, protocol violation and other reasons. 8% 7% 14% 15%

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of patients in the VIREAD and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the VIREAD arm and 283 cells/mm3 for the stavudine arm.

Through 144 weeks, 11 patients in the VIREAD group and 9 patients in the stavudine group experienced a new CDC Class C event.

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive patients. From Weeks 96 to 144 of the study, patients received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz. Patients had a mean age of 38 years (range 18—80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2—1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56—6.54). Patients were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 15.

Table 15 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)
Outcomes At Week 48 At Week 144
FTC
+VIREAD
+EFV
(N=244)
AZT/3TC
+EFV
(N=243)
FTC
+VIREAD
+EFV
(N=227) 1
AZT/3TC
+EFV
(N=229)
ResponderPatients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. 84% 73% 71% 58%
Virologic failureIncludes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. 2% 4% 3% 6%
  Rebound 1% 3% 2% 5%
  Never suppressed 0% 0% 0% 0%
  Change in antiretroviral regimen 1% 1% 1% 1%
Death <1% 1% 1% 1%
Discontinued due to adverse event 4% 9% 5% 12%
Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons. 10% 14% 20% 22%

1 Patients who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.

Through Week 48, 84% and 73% of patients in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of patients who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + VIREAD group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 patients in the emtricitabine + VIREAD group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 patients through 144 weeks).

Treatment-Experienced Patients

Study 907

Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23—1385), median baseline plasma HIV-1 RNA of 2340 (range 50—75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Changes from baseline in log10 copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure 1.

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 16.

Table 16 Outcomes of Randomized Treatment (Study 907)
Outcomes 0—24 weeks 0—48 weeks 24—48 weeks
VIREAD
(N=368)
Placebo
(N=182)
VIREAD
(N=368)
Placebo Crossover
to VIREAD
(N=170)
HIV-1 RNA <400 copies/mLPatients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively. 40% 11% 28% 30%
Virologic failurePatients with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively. 53% 84% 61% 64%
Discontinued due to adverse event 3% 3% 5% 5%
Discontinued for other reasonsIncludes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons. 3% 3% 5% 1%

At 24 weeks of therapy, there was a higher proportion of patients in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the VIREAD group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the VIREAD group.

Through Week 24, one patient in the VIREAD group and no patients in the placebo arm experienced a new CDC Class C event.

Clinical Efficacy in Patients with Chronic Hepatitis B

HBeAg-Negative Chronic Hepatitis B

Study 0102 was a Phase 3, randomized, double-blind, active-controlled study of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) patients with compensated liver function, the majority of whom were nucleoside-naive. The mean age of patients was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, patients had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.

HBeAg-Positive Chronic Hepatitis B

Study 0103 was a Phase 3, randomized, double-blind, active-controlled study of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naive patients with compensated liver function. The mean age of patients was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, patients had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.

The primary data analysis was conducted after all patients reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both studies was complete response to treatment defined as HBV DNA <400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 17).

Table 17 Histological, Virological, Biochemical, and Serological Response at Week 48
0102 (HBeAg-) 0103 (HBeAg+)
VIREAD
(N=250)
HEPSERA
(N=125)
VIREAD
(N=176)
HEPSERA
(N=90)
Complete Response 71% 49% 67% 12%
Histology
Histological ResponseKnodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. 72%
69% 74% 68%
HBV DNA
<400 copies/mL (<69 IU/mL)

93%

63%

76%

13%
ALT
Normalized ALTThe population used for analysis of ALT normalization included only patients with ALT above ULN at baseline.
76% 77% 68% 54%
Serology
HBeAg Loss/Seroconversion

NA 1

NA

20%/19%

16%/16%
HBsAg Loss/Seroconversion 0/0 0/0 3%/1% 0/0

1 NA = Not Applicable

A small proportion of nucleoside-experienced patients received VIREAD in the clinical trials: 43 patients in Study 0102 and 8 patients in Study 0103. Across both studies, 5 patients had HBV containing lamivudine-resistance associated substitutions at baseline. The numbers of patients in these subgroups were too small to establish efficacy.

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