Mechanism of Action
Adefovir is an antiviral drug.
The pharmacokinetics of
adefovir have been evaluated in healthy volunteers and patients with chronic
hepatitis B. Adefovir pharmacokinetics are similar between these populations.
Adefovir dipivoxil is a diester prodrug of the active
moiety adefovir. Based on a cross study comparison, the approximate oral
bioavailability of adefovir from HEPSERA is 59%.
Following oral administration of a 10 mg single dose of
HEPSERA to chronic hepatitis B patients (N=14), the peak adefovir plasma
concentration (Cmax) was 18.4 ± 6.26 ng/mL (mean ± SD) and occurred between
0.58 and 4.00 hours (median = 1.75 hours) post dose. The adefovir area under
the plasma concentration-time curve (AUC0-∞) was 220 ± 70.0 ng•h/mL.
Plasma adefovir concentrations declined in a biexponential manner with a
terminal elimination half-life of 7.48 ± 1.65 hours.
The pharmacokinetics of adefovir in subjects with
adequate renal function were not affected by once daily dosing of 10 mg HEPSERA
over seven days. The impact of long-term once daily administration of 10 mg
HEPSERA on adefovir pharmacokinetics has not been evaluated.
Effects of Food on Oral Absorption
Adefovir exposure was unaffected when a 10 mg single dose
of HEPSERA was administered with food (an approximately 1000 kcal high-fat
meal). HEPSERA may be taken without regard to food.
In vitro binding of adefovir to human plasma or human
serum proteins is less than or equal to 4% over the adefovir concentration
range of 0.1 to 25 μg/mL. The volume of distribution at steady-state
following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and
352 ± 9 mL/kg, respectively.
Metabolism and Elimination
Following oral administration, adefovir dipivoxil is
rapidly converted to adefovir. Forty-five percent of the dose is recovered as
adefovir in the urine over 24 hours at steady state following 10 mg oral doses
of HEPSERA. Adefovir is renally excreted by a combination of glomerular
filtration and active tubular secretion [See DRUG INTERACTIONS].
Assessment of Drug Interactions
Adefovir dipivoxil is rapidly converted to adefovir in
vivo. At concentrations substantially higher (greater than 4000-fold) than
those observed in vivo, adefovir did not inhibit any of the common human CYP450
enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not a
substrate for these enzymes. However, the potential for adefovir to induce
CYP450 enzymes is unknown. Based on the results of these in vitro experiments
and the renal elimination pathway of adefovir, the potential for CYP450
mediated interactions involving adefovir as an inhibitor or substrate with
other medicinal products is low.
The pharmacokinetics of adefovir have been evaluated in
healthy adult volunteers following multiple dose administration of HEPSERA (10
mg once daily) in combination with lamivudine (100 mg once daily) (N=18),
trimethoprim/sulfamethoxazole (160/800 mg twice daily) (N=18), acetaminophen
(1000 mg four times daily) (N=20), ibuprofen (800 mg three times daily) (N=18),
and enteric coated didanosine (400 mg) (N=21). The pharmacokinetics of adefovir
have also been evaluated in post-liver transplantation patients following multiple
dose administration of HEPSERA (10 mg once daily) in combination with
tacrolimus (N=16). The pharmacokinetics of adefovir have been evaluated in
healthy volunteers following single dose pegylated interferon α-2a
(PEGIFN) (180 μg) (N=15).
Adefovir did not alter the pharmacokinetics of
lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, ibuprofen, enteric
coated didanosine (didanosine EC), or tacrolimus. The evaluation of the effect
of adefovir on the pharmacokinetics of pegylated interferon α-2a was
inconclusive due to the high variability of pegylated interferon alpha-2a.
The pharmacokinetics of adefovir were unchanged when
HEPSERA was coadministered with lamivudine, trimethoprim/sulfamethoxazole,
acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and
pegylated interferon α-2a. When HEPSERA was coadministered with ibuprofen
(800 mg three times daily) increases in adefovir Cmax (33%), AUC (23%) and
urinary recovery were observed. This increase appears to be due to higher oral
bioavailability, not a reduction in renal clearance of adefovir.
Apart from lamivudine, trimethoprim/sulfamethoxazole, and
acetaminophen, the effects of coadministration of HEPSERA with drugs that are
excreted renally, or other drugs known to affect renal function have not been
The effect of adefovir on cyclosporine concentrations is
No drug interaction studies have been performed in
adolescent patients 12 to less than 18 years of age.
The pharmacokinetics of adefovir were similar in male and
The pharmacokinetics of adefovir have been shown to be
comparable in Caucasians and Asians. Pharmacokinetic data are not available for
other racial groups.
Pharmacokinetic studies have not been conducted in the
The pharmacokinetics of adefovir were assessed from drug
plasma concentrations in 53 HBeAg positive hepatitis B pediatric patients with
compensated liver disease. The exposure of adefovir following a 48 week daily
treatment with adefovir dipivoxil 10 mg tablet in pediatric patients 12 to less
than 18 years of age (Cmax = 23.3 ng/mL and AUC024 = 248.8 ng·h/mL) was
comparable to that observed in adult patients.
In adults with moderately or severely impaired renal
function or with end-stage renal disease (ESRD) requiring hemodialysis, Cmax, AUC,
and half-life (T½) were increased compared to adults with normal renal
function. It is recommended that the dosing interval of HEPSERA be modified in
these patients [See DOSAGE AND ADMINISTRATION].
The pharmacokinetics of adefovir in non-chronic hepatitis
B patients with varying degrees of renal impairment are described in Table 3.
In this study, subjects received a 10 mg single dose of HEPSERA.
Table 3 : Pharmacokinetic Parameters (Mean ± SD)
of Adefovir in Patients with Varying Degrees of Renal Function
|Renal Function Group
|Baseline creatinine clearance (mL/min)
|| > 80 (N=7)
||17.8 ± 3.22
||22.4 ± 4.04
||28.5 ± 8.57
||51.6 ± 10.3
|AUC 0-∞ (ng•h/mL)
||201 ± 40.8
||266 ± 55.7
||455 ± 176
||1240 ± 629
||469 ± 99.0
||356 ± 85.6
||237 ± 118
||91.7 ± 51.3
||231 ± 48.9
||148 ± 39.3
||83.9 ± 27.5
||37.0 ± 18.4
A four-hour period of
hemodialysis removed approximately 35% of the adefovir dose. The effect of
peritoneal dialysis on adefovir removal has not been evaluated.
The pharmacokinetics of adefovir have not been studied in
adolescent patients with renal dysfunction [See Use In Specific Populations].
The pharmacokinetics of adefovir following a 10 mg single
dose of HEPSERA have been studied in non-chronic hepatitis B patients with
hepatic impairment. There were no substantial alterations in adefovir
pharmacokinetics in patients with moderate and severe hepatic impairment
compared to unimpaired patients. No change in HEPSERA dosing is required in
patients with hepatic impairment.
Mechanism of Action
Adefovir is an acyclic nucleotide analog of adenosine
monophosphate which is phosphorylated to the active metabolite adefovir
diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA
polymerase (reverse transcriptase) by competing with the natural substrate
deoxyadenosine triphosphate and by causing DNA chain termination after its
incorporation into viral DNA. The inhibition constant (Ki) for adefovir
diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a
weak inhibitor of human DNA polymerases α and γ with Ki values of
1.18 μM and 0.97 μM, respectively.
The concentration of adefovir that inhibited 50% of viral
DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from
0.2 to 2.5 μM. The combination of adefovir with lamivudine showed additive
Clinical isolates with genotypic changes conferring
reduced susceptibility in cell culture to nucleoside analog reverse
transcriptase inhibitors for the treatment of HBV infection have been observed.
Long-term resistance analyses performed by genotyping samples from all adefovir
dipivoxil-treated patients with detectable serum HBV DNA demonstrated that
amino acid substitutions rtN236T and rtA181T/V have been observed in
association with adefovir resistance. In cell culture, the rtN236T substitution
demonstrated 4-to 14-fold, the rtA181V substitution 2.5-to 4.2-fold, and the
rtA181T substitution 1.3-to 1.9-fold reduced susceptibility to adefovir.
In HBeAg-positive nucleoside-naÃ¯ve patient isolates
(Study GS-98-437, N=171), no adefovir resistance-associated substitutions were
observed at Week 48. Sixty-five patients continued on long term treatment after
a median duration on adefovir dipivoxil of 235 weeks (range 110–279 weeks).
Isolates from 16 of 38 (42%) patients developed adefovir resistance-associated
substitutions in the setting of virologic failure (confirmed increase of at
least 1 log10 HBV DNA copies/mL above nadir or never suppressed below 103 copies/mL).
The substitutions included rtN236T (N=2), rtA181V (N=4), rtA181T (N=3),
rtA181T+rtN236T (N=5), and rtA181V+rtN236T (N=2). In HBeAgnegative
nucleoside-naÃ¯ve patients (Study GS-98-438), isolates from 30 patients were
identified with adefovir resistance-associated substitutions with a cumulative
probability of 0%, 3%, 11%, 19%, and 30% at 48, 96, 144, 192, and 240 weeks,
respectively. Of those 30 patients, 22 had a confirmed increase of at least 1
log10 HBV DNA copies/mL above nadir or never achieved HBV DNA levels below 103
copies/mL; an additional 8 patients had adefovir resistance-associated
substitutions without virologic failure. In addition, the long term (4 to 5
years) development of resistance to adefovir dipivoxil was significantly lower
in patients who had serum HBV DNA below the limit of quantification (less than
1,000 copies/mL) at Week 48 as compared to patients who had serum HBV DNA above
1,000 copies/mL at Week 48.
In an open-label study of pre-and post-liver
transplantation patients (Study GS-98-435), isolates from 129 patients with
clinical evidence of lamivudine-resistant hepatitis B virus at baseline were
evaluated for adefovir resistance-associated substitutions. The incidence of
adefovir resistance-associated (rtN236T or rtA181T/V) substitutions was 0% at
48 weeks. Isolates from four patients developed the rtN236T substitution after
72 weeks of adefovir dipivoxil therapy. Development of the rtN236T substitution
was associated with serum HBV DNA rebound. All 4 patients who developed the
rtN236T substitution in their HBV had discontinued lamivudine therapy before
the development of genotypic resistance and all 4 lost the lamivudine
resistance-associated substitutions present at baseline. In a study of 35
HIV/HBV co-infected patients with lamivudineresistant HBV (Study 460i) who
added adefovir dipivoxil to lamivudine, no adefovir resistance-associated
substitutions were observed in HBV isolates from 15/35 patients tested up to
144 weeks of therapy.
Clinical resistance in pediatric patients
In a Phase 3 pediatric Study GS-US-103-518, HBV isolates
from 49 of 56 pediatric subjects (aged 12 to 17 years) had serum HBV DNA
greater than 169 copies/mL and were evaluated for adefovir
resistance-associated substitutions. rtN236T and/or rtA181V adefovir
resistance-associated substitutions were not observed at Week 48. However, the
rtA181T substitution was present in baseline and Week 48 isolates from 2
Recombinant HBV variants containing
lamivudine-resistance-associated substitutions (rtL180M, rtM204I, rtM204V,
rtL180M + rtM204V, rtV173L + rtL180M + rtM204V) were susceptible to adefovir in
cell culture. Adefovir dipivoxil has also demonstrated anti-HBV activity
(median reduction in serum HBV DNA of 4.1 log10 copies/mL) in patients with HBV
containing lamivudine-resistance-associated substitutions (Study 435). Adefovir
also demonstrated in cell culture activity against HBV variants with entecavir
resistance-associated substitutions (rtT184G, rtS202I, rtM250V). HBV variants
with DNA polymerase substitutions rtT128N and rtR153Q or rtW153Q associated
with resistance to hepatitis B virus immunoglobulin were susceptible to
adefovir in cell culture.
HBV variants expressing the adefovir
resistance-associated substitution rtN236T showed no change in susceptibility
to entecavir in cell culture, and a 2-to 3-fold decrease in lamivudine
susceptibility. HBV mutants with the adefovir resistance-associated
substitution rtA181V showed a range of decreased susceptibilities to lamivudine
of 1-to 14-fold and a 12-fold decrease in susceptibility to entecavir. In
patients whose HBV expressed the rtA181V substitution (N=2) or the rtN236T
substitution (N=3), a reduction in serum HBV DNA of 2.4 to 3.1 and 2.0 to 5.1
log10 copies/mL, respectively, was observed when treatment with lamivudine was
added to treatment with adefovir dipivoxil.
Animal Toxicology and/or Pharmacology
Animal reproduction studies were conducted in rats and
rabbits with orally administered adefovir dipivoxil and intravenously
In rats and rabbits, no embryotoxicity or teratogenicity
was shown from oral administration of adefovir dipivoxil at maternal doses
producing systemic exposures approximately 23 times (rats) and 40 times
(rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.
When pregnant rats were administered intravenous adefovir
at maternally toxic doses associated with systemic exposure 38 times that in
humans, embryotoxicity and an increased incidence of fetal malformations
(anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were
observed. No adverse effects on development were seen with intravenous adefovir
administered to pregnant rats at a systemic exposure 12 times that in humans.
Animal Toxicology Studies
Renal tubular nephropathy characterized by histological
alterations and/or increases in BUN and serum creatinine was the primary
dose-limiting toxicity associated with administration of adefovir dipivoxil in
animals. Nephrotoxicity was observed in animals at systemic exposures
approximately 3–10 times higher than those in humans at the recommended
therapeutic dose of 10 mg/day.
Studies 437 and 438 (Pivotal Studies)
HBeAg-Positive Chronic Hepatitis B
Study 437 was a randomized, double-blind,
placebo-controlled, three-arm study in patients with HBeAg-positive chronic
hepatitis B that allowed for a comparison between placebo and HEPSERA. The
median age of patients was 33 years. Seventy-four percent were male, 59% were
Asian, 36% were Caucasian, and 24% had prior interferon-α treatment. At
baseline, patients had a median total Knodell Histology Activity Index (HAI)
score of 10, a median serum HBV DNA level as measured by the Roche Amplicor
Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 copies/mL) of 8.36
log10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.
HBeAg-Negative (Anti-HBe Positive/HBV DNA Positive)
Chronic Hepatitis B
Study 438 was a randomized, double-blind,
placebo-controlled study in patients who were HBeAg-negative at screening, and
anti-HBe positive. The median age of patients was 46 years. Eighty-three
percent were male, 66% were Caucasian, 30% were Asian and 41% had prior
interferon-α treatment. At baseline, the median total Knodell HAI score
was 10, the median serum HBV DNA level as measured by the Roche Amplicor
Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log10 copies/mL, and the
median ALT was 2.3 times the upper limit of normal.
The primary efficacy endpoint in both studies was
histological improvement at Week 48; results of which are shown in Table 4.
Table 4 : Histological Response at Week 48a
|HEPSERA 10 mg
|HEPSERA 10 mg
|aIntent-to-Treat population (patients with
≥ 1 dose of study drug) with assessable baseline biopsies.
bHistological improvement defined as ≥ 2 point decrease in the
Knodell necro-inflammatory score with no worsening of the Knodell fibrosis
Table 5 illustrates the changes in Ishak Fibrosis Score
by treatment group.
Table 5 : Changes in Ishak Fibrosis Score at Week 48
|Number of Adequate Biopsy Pairs
|HEPSERA 10 mg (N=152)
||HEPSERA 10 mg (N=113)
|Ishak Fibrosis Score Improveda
|aChange of 1 point or more in Ishak Fibrosis Score.
At Week 48, improvement was
seen with respect to mean change in serum HBV DNA (log10 copies/mL),
normalization of ALT, and HBeAg seroconversion as compared to placebo in
patients receiving HEPSERA (Table 6).
Table 6 : Change in Serum
HBV DNA, ALT Normalization, and HBeAg Seroconversion at Week 48
|HEPSERA 10 mg
|HEPSERA 10 mg
|Mean change ± SD in serum HBV DNA from baseline (log10 copies/mL)
||–3.57 ± 1.64
||–0.98 ± 1.32
||–3.65 ± 1.14
||–1.32 ± 1.25
|aPatients with HBeAg-negative disease cannot undergo HBeAg
Treatment Beyond 48 Weeks
In Study 437, continued
treatment with HEPSERA to 72 weeks resulted in continued maintenance of mean
reductions in serum HBV DNA observed at Week 48. An increase in the proportion
of patients with ALT normalization was also observed in Study 437. The effect
of continued treatment with HEPSERA on seroconversion is unknown.
In Study 438, patients who
received HEPSERA during the first 48 weeks were re-randomized in a blinded
manner to continue on HEPSERA or receive placebo for an additional 48 weeks. At
Week 96, 50 of 70 (71%) of patients who continued treatment with HEPSERA had
undetectable HBV DNA levels (less than 1000 copies/mL), and 47 of 64 (73%) of
patients had ALT normalization. HBV DNA and ALT levels returned towards
baseline in most patients who stopped treatment with HEPSERA.
From 141 eligible patients, there were 125 (89%) patients
in Study 438 who chose to continue HEPSERA for up to 192 weeks or 240 weeks (4
years or 5 years). As these patients had already received HEPSERA for at least
48 weeks and appeared to be experiencing a benefit, they are not necessarily
representative of patients initiating HEPSERA. Of these patients, 89/125 (71%)
and 47/70 (67%) had an undetectable HBV DNA level (less than 1000 copies/mL) at
Week 192 and Week 240, respectively. Of the patients who had an elevated ALT at
baseline, 77/104 (74%) and 42/64 (66%) had a normal ALT at Week 192 and Week
240, respectively. Six (5%) patients experienced HBsAg loss.
Study 435 (Pre-and Post-Liver Transplantation Patients)
HEPSERA was also evaluated in an open-label, uncontrolled
study of 467 chronic hepatitis B patients pre-(N=226) and post-(N=241) liver
transplantation with clinical evidence of lamivudine-resistant hepatitis B
virus (Study 435). At baseline, 60% of pre-liver transplantation patients were
classified as Child-Pugh-Turcotte score of Class B or C. The median baseline
HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000
copies/mL) was 7.4 and 8.2 log10 copies/mL, and the median baseline ALT was 1.8
and 2.0 times the upper limit of normal in pre-and post-liver transplantation
patients, respectively. Results of this study are displayed in Table 7.
Treatment with HEPSERA resulted in a similar reduction in serum HBV DNA
regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations
at baseline. The significance of the efficacy results listed in Table 7 as they
relate to clinical outcomes is not known.
Table 7 : Efficacy in Pre-and Post-Liver
Transplantation Patients at Week 48
|Mean change ± SD in HBV DNA from baseline (log10 copies/mL)
||–3.7 ± 1.6 (N=117)
||–4.0 ± 1.6 (N=164)
|Proportion with undetectable HBV DNA (
|Stable or improved Child-Pugh-Turcotte score
|Normalization of:c :ALT
|aData are missing for 29% (HBV DNA) and 37% to
45% (CPT Score, Normalization of ALT, Albumin, Bilirubin, and PT) of total
patients enrolled in the study.
bDenominator is the number of patients with serum HBV DNA
≥ 1000 copies/mL at baseline using the Roche Amplicor Monitor PCR Assay
(LLOQ = 1000 copies/mL) and non-missing value at Week 48.
cDenominator is patients with abnormal values at baseline and
non-missing value at Week 48.
Study 461 (Clinical Evidence of Lamivudine Resistance)
In Study 461, a double-blind, active controlled study in
59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant
hepatitis B virus, patients were randomized to receive either HEPSERA
monotherapy or HEPSERA in combination with lamivudine 100 mg or lamivudine 100
mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by
the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41
log10 copies/mL for patients treated with HEPSERA and 3.46 ± 1.10 log10 copies/mL
for patients treated with HEPSERA in combination with lamivudine. There was a
mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients
receiving lamivudine alone. ALT normalized in 47% of patients treated with
HEPSERA, in 53% of patients treated with HEPSERA in combination with
lamivudine, and 5% of patients treated with lamivudine alone. The significance of
these findings as they relate to clinical outcomes is not known.
Study 518 (Pediatric Study)
Study 518 was a double-blind, placebo-controlled, study
in which 173 pediatric patients (ages 2 to less than 18 years) with chronic
hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving
adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by
prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than
12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All
patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts
1 and 2 received an investigational suspension formulation (0.3 mg/kg/day
cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint
was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of
In cohort 3 (N=83), significantly more patients treated
with HEPSERA achieved the primary efficacy endpoint at the end of 48 weeks of
blinded treatment (23%) when compared to placebo-treated patients (0%). The
proportion of patients from cohorts 1 and 2 who responded to treatment with
adefovir dipivoxil was not statistically significant when compared to the
placebo arm, although the adefovir plasma concentrations in these patients were
comparable to those observed in older patients. Overall, 22 of 115 (19%) of
pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of
placebo treated patients responded to treatment by Week 48 [See ADVERSE
REACTIONS, Use In Specific Populations].