Mechanism of Action
Tenofovir disoproxil fumarate is an antiviral drug.
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 subjects is approximately 25%. Following oral administration of a single
dose of VIREAD 300 mg to HIV-1 infected subjects in the fasted state, maximum
serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC
values are 0.30 ± 0.09μg/mL and 2.29
± 0.69 μg•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 μg/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 μg/mL and 3.32 ± 1.37 μg•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
subjects.
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 subjects with renal impairment [See WARNINGS AND
PRECAUTIONS]. In subjects 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
Tenofovira in Subjects 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 (μg/mL) |
0.34 ±0.03 |
0.33 ± 0.06 |
0.37 ±0.16 |
0.60 ±0.19 |
| AUC0-∞ (*mu;g•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 |
| a 300 mg, single dose of VIREAD |
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
subjects with moderate to severe hepatic impairment. There were no substantial
alterations in tenofovir pharmacokinetics in subjects with hepatic impairment
compared with unimpaired subjects. 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.
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 Tenofovira in the Presence of the Coadministered Drug
| Coadministered Drug |
Dose of Coadministered Drug (mg) |
N |
% Change of Tenofovir Pharmacokinetic Parametersb
(90% CI) |
| Cmax |
AUC |
Cmin |
| Abacavir |
300 once |
8 |
⇔ |
⇔ |
NC |
| Atazanavirc |
400 once daily x 14 days |
33 |
↑1 4
(↑8 to ↑ 20) |
↑24
(↑ 21 to ↑28) |
↑2 2
(↑ 15 to ↑30) |
| Didanosine (enteric-coated) |
400 once |
25 |
⇔ |
⇔ |
⇔ |
| Didanosine (buffered) |
250 or 400 once daily x 7 days |
14 |
⇔ |
⇔ |
⇔ |
| Efavirenz |
600 once daily x 14 days |
29 |
⇔ |
⇔ |
⇔ |
| Emtricitabine |
200 once daily x 7 days |
17 |
⇔ |
⇔ |
⇔ |
| Entecavir |
1 mg once daily x 10 days |
28 |
⇔ |
⇔ |
⇔ |
| Indinavir |
800 three times daily x 7 days |
13 |
↑1 4
(↓ 3 to ↑33) |
⇔ |
⇔ |
| Lamivudine |
150 twice daily x 7 days |
15 |
⇔ |
⇔ |
⇔ |
| Lopinavir/Ritonavir |
400/100 twicedaily x 14 days |
24 |
⇔ |
↑32
(↑25 to ↑38) |
↑51
(↑37 to ↑66) |
| Nelfinavir |
1250 twice daily x 14 days |
29 |
⇔ |
⇔ |
⇔ |
| Saquinavir/Ritonavir |
1000/100 twice daily x 14 days |
35 |
⇔ |
⇔ |
f 23
(t 16 to t 30) |
| Tacrolimus |
0.05 mg/kg twice daily x 7 days |
21 |
↑13
(↑1 to ↑ 27) |
⇔ |
⇔ |
a Subjects received VIREAD 300 mg once daily.
b Increase = ↑; Decrease = ↓ No Effect = ⇔;
NC = Not Calculated
c Reyataz Prescribing Information |
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
Parametersa (90% CI) |
| Cmax |
AUC |
Cmin |
| Abacavir |
300 once |
8 |
↑ 12
(↓1 to ↑ 26) |
⇔ |
NA |
| Atazanavirb |
400 once daily x14 days |
34 |
↓21
(↓27 to ↓14) |
↓25
(↓30 to ↓ 19) |
↓40
(↓48 to ↓ 32) |
| Atazanavirb |
Atazanavir/ Ritonavir 300/100 once daily x 42 days |
10 |
↓28
(↓ 50 to ↑5) |
↓25c
(↓ 42 to ↓3) |
↓23c
(↓46 to ↑10) |
| Efavirenz |
600 once daily x14 days |
30 |
⇔ |
⇔ |
⇔ |
| Emtricitabine |
200 once daily x 7 days |
17 |
⇔ |
⇔ |
↑20
(↑12 to ↑29) |
| Entecavir |
1 mg once daily x 10 days |
28 |
⇔ |
↑13
(↑11 to ↑15) |
⇔ |
| Indinavir |
800 three times daily x 7 days |
12 |
↓11
(↓30 to ↑12) |
⇔ |
⇔ |
| Lamivudine |
150 twice daily x 7 days |
15 |
↓24
(↓3 4 to ↓12) |
⇔ |
⇔ |
| Lopinavir |
Lopinavir/Ritonavir 400/100 twice daily x14
days |
24 |
⇔ |
⇔ |
⇔ |
| Ritonavir |
⇔ |
⇔ |
⇔ |
| Methadoned |
40-110 once daily x 14 dayse |
13 |
⇔ |
⇔ |
|
| Nelfinavir M8 metabolite |
1250 twice daily x 14 days |
29 |
⇔ |
⇔ |
⇔ |
| Oral Contraceptivesf |
Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) once
daily x 7 days |
20 |
⇔ |
⇔ |
⇔ |
| Ribavirin |
600 once |
22 |
⇔ |
⇔ |
NA |
| Saquinavir |
Saquinavir/ Ritonavir 1000/100 twice daily
x14 days |
|
↑22
(↑6 to ↑41) |
↑29g
(↑12 to ↑48) |
↑47g
(↑23 to ↑76) |
| Ritonavir |
32 |
⇔ |
⇔ |
↑23
(↑3 to ↑46) |
| Tacrolimus |
0.05 mg/kg twice daily x 7 days |
21 |
⇔ |
⇔ |
⇔ |
a Increase = ↑; Decrease = ↓; No Effect
= ⇔; NA = Not Applicable
b Reyataz Prescribing Information
c. 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.
d R-(active), S- and total methadone exposures were equivalent
when dosed alone or with VIREAD.
e Individual subjects were maintained on their stable methadone
dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs
or symptoms) were reported.
f Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically
active metabolite) exposures were equivalent when dosed alone or with
VIREAD.
g 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 Administrationa |
N |
%Difference (90% CI) vs. Didanosine 400 mg
Alone,Fastedb |
| Cmax |
AUC |
| Buffered tablets |
| 400 once dailyc x 7 days |
Fasted 1 hour after didanosine |
14 |
↑2 8
(↑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 |
↑6 4
(↑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) |
a Administration with food was with a light meal
(~373 kcal, 20% fat).
b Increase = ↑; Decrease =↓, No Effect = ⇔
c Includes 4 subjects weighing < 60 kg receiving ddl 250
mg. |
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 a, p, and mitochondrial DNA polymerase y.
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 0.04μ M to 8.5μM. 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 0.5μM to 2.2 μM) and strain specific
activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5
μM).
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 subjects (VIREAD +
lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See Clinical
Studies], genotypic analyses of isolates from subjects 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 subjects 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 subjects (VIREAD + EMTRIVA + efavirenz versus
zidovudine (AZT)/lamivudine (3TC) + efavirenz) [See Clinical Studies],
genotypic analysis performed on HIV-1 isolates from all confirmed virologic
failure subjects 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
subject isolates in the VIREAD + EMTRIVA group and in 10/29 analyzed subject
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.
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 subjects (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.
In Studies 902 and 907 conducted in treatment-experienced subjects (VIREAD
+ Standard Background Therapy (SBT) compared to Placebo + SBT) [See Clinical
Studies], 14/304 (5%) of the VIREAD-treated subjects 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
subjects 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 subjects 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
subjects 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. Subjects whose virus expressed an L74V substitution without zidovudine
resistance associated substitutions (N=8) had reduced response to VIREAD. Limited
data are available for subjects whose virus expressed a Y115F substitution (N=3),
Q151M substitution (N=2), orT69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to
VIREAD was not reduced in subjects with HIV-1 that expressed the
abacavir/emtricitabine/lamivudine resistanceassociated M184V substitution.
HIV-1 RNA responses among these subjects 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 subjects
participating in two controlled trials. Phenotypic analysis of baseline HIV-1
from subjects 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)a
| Baseline VIREAD Susceptibilityb |
Change in HIV-1 RNAC (N) |
| < 1 |
-0.74 (35) |
| > 1 and ≤ 3 |
-0.56 (49) |
| > 3 and ≤ 4 |
-0.3 (7) |
| > 4 |
-0.12(9) |
a Tenofovir susceptibility was determined by
recombinant phenotypic Antivirogram assay (Virco).
b Fold change in susceptibility from wild-type.
c Average HIV-1 RNA change from baseline through Week 24 (DAVG24)
in log10 copies/mL |
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 μM, with CC50 (50% cytotoxicity concentration) values > 100 μM.
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
Cumulative VIREAD genotypic resistance analysis of paired
pre-treatment and ontreatment isolates was performed using an as-treated
analysis. Subjects remaining viremic with HBV DNA > 400 copies/mL at the last
evaluable study visit after 96 weeks of cumulative treatment (16%[26/160] of
HBeAg positive subjects in Study 103 and 3% [8/234] of HBeAg negative subjects
in Study 102) were evaluated for genotypic resistance. These 34 subjects with
viremia were primarily treatment-naive and received VIREAD for up to 96 weeks;
of these, 65% (17/26) of HBeAg-positive and 13% (1/8) of HBeAg-negative
subjects had a baseline viral load of > 9 log10 copies/mL.
In addition, 16 of the 84 HBeAg-positive subjects who
received 48 weeks of HEPSERA and then switched to VIREAD for up to 48 weeks,
and 18 of 53 Hepsera treatment experienced subjects from an ongoing Phase 2
study who received up to 48 weeks of VIREAD monotherapy and who had plasma HBV
DNA > 400 copies/mL, were included in the resistance analysis. Subjects in
the Phase 2 study were previously treated for 24 to 96 weeks with HEPSERA for
chronic HBV infection and had plasma HBV DNA levels ≥ 1,000 copies/mL at
screening.
In the three VIREAD-treatment studies, paired genotypic data
were obtained for 55 of 68 viremic subjects. No specific amino acid
substitutions in the HBV reverse transcriptase domain occurred at a sufficient
frequency to be associated with resistance to VIREAD (genotypic or phenotypic
analyses).
In the three VIREAD-treatment studies, prior to treatment
with VIREAD, 13 and 10 subjects had HBV harboring adefovir
resistance-associated substitutions (rtA181T/V and/or rtN236T) or lamivudine
resistance-associated substitution (rtM204l/V), respectively. Following up to
96 weeks of VIREAD treatment, 11 of the 13 subjects with adefovir-resistant HBV
and 8 of the 10 subjects with lamivudine-resistant HBV achieved virologic
suppression (HBV DNA < 400 copies/mL). Two of the 4 subjects harboring both the
rtA181T/V and rtN236T substitutions remained viremic following 24 weeks of VIREAD
monotherapy.
Cross Resistance
Cross-resistance has been observed among HBV reverse
transcriptase inhibitors.
In cell based assays, HBV strains expressing the rtV173L,
rtL180M, and rtM204l/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 rtM204l/V double
substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/l,
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, rtS202l and rtM204V
together had a 6.9-fold reduction in susceptibility to tenofovir.
HBV strains expressing the adefovir resistance-associated
substitutions rtA181V and/or (1N236T 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.
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-Naive 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
subjects. Subjects 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). Subjects were stratified by baseline HIV-1 RNA
and CD4+ cell count. Forty-three percent of subjects 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)
| Outcomes |
At Week 48 |
At Week 144 |
VIREAD+3TC
+EFV
(N=299) |
d4T+3TC
+EFV
(N=301) |
VIREAD+
3TC+EFV
(N=299) |
d4T+3TC
+EFV
(N=301) |
| Respondera |
79% |
82% |
68% |
62% |
| Virologic failureb |
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 reasonsc |
8% |
7% |
14% |
15% |
a Subjects achieved and maintained confirmed
HIV-1 RNA < 400 copies/mL through Week 48 and 144.
b Includes confirmed viral rebound and failure to achieve confirmed
< 400 copies/mL through Week 48 and 144.
c Includes lost to follow-up, subject's withdrawal, noncompliance,
protocol violation and other reasons. |
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 subjects 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 subjects in the VIREAD group and 9
subjects 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, activecontrolled 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 subjects. From Weeks 96 to 144 of the study, subjects
received a fixed-dose combination of emtricitabine and tenofovir DF with
efavirenz in place of emtricitabine + VIREAD with efavirenz. Subjects 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). Subjects were stratified by baseline CD4+ cell count ( < or ≥ 200 cells/mm³); 41% had CD4+cell counts < 200 cells/mm³ and 51% of
subjects had baseline viral loads > 100,000 copies/mL. Treatment outcomes
through 48 and 144 weeks for those subjects 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 Week144 |
FTC+
VIREAD
+EFV
(N=244) |
AZT/3TC
+EFV
(N=243) |
FTC+
VIREAD
+EFV
(N=227)a |
AZT/3TC
+EFV
(N=229)a |
| Responderb |
84% |
73% |
71% |
58% |
| Virologic failurec |
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 reasonsd |
10% |
14% |
20% |
22% |
a Subjects 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.
b Subjects achieved and maintained confirmed HIV-1 RNA < 400
copies/mL through Weeks 48 and 144.
c Includes confirmed viral rebound and failure to achieve confirmed
< 400 copies/mL through Weeks 48 and 144.
d Includes lost to follow-up, subject withdrawal, noncompliance,
protocol violation and other reasons. |
Through Week 48, 84% and 73% of subjects 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 subjects 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 subjects 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 subjects in the emtricitabine + VIREAD
group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC
Class C event (10 and 6 subjects 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 subjects. After 24 weeks of
blinded study treatment, all subjects continuing on study were offered
open-label VIREAD for an additional 24 weeks. Subjects 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 subjects 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.
Figure 1 : Mean Change from Baseline in Plasma HIV-1 RNA
(log10 copies/mL) Through Week 48 (Study 907; All Available Data)†
The percent of subjects with HIV-1 RNA < 400 copies/mL and
outcomes of subjects through 48 weeks are summarized in Table 16.
Table 16 : Outcomes of Randomized Treatment (Study 907)
| Outcomes |
0-24weeks |
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/mLa |
40% |
11% |
28% |
30% |
| Virologic failureb |
53% |
84% |
61% |
64% |
| Discontinued due to adverse event |
3% |
3% |
5% |
5% |
| Discontinued for other reasonsc |
3% |
3% |
5% |
1% |
a Subjects with HIV-1 RNA < 400 copies/mL and
no prior study drug discontinuation at Week 24 and 48 respectively.
b Subjects with HIV-1 RNA ≥ 400 copies/mL efficacy failure
or missing HIV-1 RNA at Week 24 and 48 respectively.
c Includes lost to follow-up, subject withdrawal, noncompliance,
protocol violation and other reasons. |
At 24 weeks of therapy, there was a higher proportion of subjects 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 subject in the VIREAD group and no
subjects 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+) subjects with compensated liver function, the majority of
whom were nucleoside-naive. The mean age of subjects 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, subjects 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-naïve subjects with compensated liver function. The mean age
of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian,
16% had previously received alphainterferon therapy, and < 5% were nucleoside
experienced. At baseline, subjects 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 subjects
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 Histology |
71% |
49% |
67% |
12% |
| Histological Responsea |
72% |
69% |
74% |
68% |
| HBV DNA |
| < 400 copies/mL ( < 69 lU/mL) |
93% |
63% |
76% |
13% |
| ALT |
| Normalized ALTb |
76% |
77% |
68% |
54% |
| Serology |
| HBeAg Loss/Seroconversion |
NA C |
NA C |
20%/19% |
16%/16% |
| HBsAg Loss/Seroconversion |
0/0 |
0/0 |
3%/1% |
0/0 |
a Knodell necroinflammatory score
improvement of at least 2 points without worsening in Knodell fibrosis.
b The population used for analysis of ALT normalization included
only subjects with ALT above ULN at baseline.
c NA = Not Applicable |
Treatment beyond 48 Weeks
In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive),
subjects rolled over with no interruption in treatment to open-label VIREAD
through Week 96 after receiving double-blind treatment for 48 weeks (either
VIREAD or HEPSERA). At Week 72 or thereafter, emtricitabine could be added to
VIREAD in subjects who had detectable HBV DNA.
In Study 0102, 90% of subjects who were randomized to VIREAD
completed 96 weeks of treatment. Among subjects randomized to VIREAD followed
by open-label treatment with VIREAD, 89% had undetectable HBV DNA ( < 400
copies/mL), and 71% had ALT normalization at Week 96. In the group of subjects
randomized to HEPSERA followed by open-label treatment with VIREAD, 88%
completed 96 weeks of treatment; 96% of this cohort had undetectable HBV DNA
( < 400 copies/mL) and 71 % had ALT normalization at Week 96. Emtricitabine
was added to VIREAD in 2 ( < 1%) subjects initially randomized to VIREAD and
none of those randomized to HEPSERA. No subject in either treatment group
experienced HBsAg loss/seroconversion through Week 96.
In Study 0103, 82% of subjects randomized to VIREAD
completed 96 weeks of treatment. Among subjects randomized to VIREAD, 81% had
undetectable HBV DNA ( < 400 copies/mL), 64% had ALT normalization, 27% had
HBeAg loss (23% seroconversion to anti-HBe antibody), and 5% had HBsAg loss (4%
seroconversion to anti-HBs antibody) through Week 96. Among subjects randomized
to HEPSERA followed by up to 48 weeks of open-label treatment with VIREAD, 92%
of subjects completed 96 weeks of treatment; 76% had undetectable HBV DNA ( <
400 copies/mL), 67% had ALT normalization, 24% had HBeAg loss (21%
seroconversion to anti-HBe antibody), and 6% experienced HBsAg loss (5%
seroconversion to anti-HBs antibody) through Week 96. Emtricitabine was added
to VIREAD in 15 (9%) subjects randomized to VIREAD, and in 13 (14%) subjects
randomized to HEPSERA.
Across the combined HBV treatment studies, the number of
subjects with lamivudine- or adefovir-resistance associated substitutions at
baseline was too small to establish efficacy in this subgroup.
Last updated on RxList: 10/29/2009