Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF08.

Mechanism of action
Adefovir dipivoxil is an oral prodrug of adefovir, an acyclic nucleotide phosphonate analogue of adenosine monophosphate, which is actively transported into mammalian cells where it is converted by host enzymes to adefovir diphosphate. Adefovir diphosphate inhibits viral polymerases by competing for direct binding with the natural substrate (deoxyadenosine triphosphate) and, after incorporation into viral DNA, causes DNA chain termination.

Pharmacodynamic effects
Adefovir diphosphate selectively inhibits HBV DNA polymerases at concentrations 12-, 700-, and 10-fold lower than those needed to inhibit human DNA polymerases α, β, and γ, respectively.
Adefovir diphosphate has an intracellular half-life of 12 to 36 hours in activated and resting lymphocytes.

Adefovir is active against hepadnaviruses in vitro, including all common forms of lamivudine-resistant HBV (rtL180M, rtM204I, rtM204V, rtL180M/rtM204V), famciclovir-associated mutations (rtV173L, rtP177L, rtL180M, rtT184S or rtV207I) and hepatitis B immunoglobulin escape mutations (rtT128N and rtW153Q), and in in vivo animal models of hepadnavirus replication.

Clinical efficacy and safety
The demonstration of the benefit of adefovir dipivoxil is based on histological, virological, biochemical, and serological responses in adults with:

•     HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease.

•     lamivudine-resistant HBV with either compensated or decompensated liver disease, including patients pre- and post-liver transplantation or co-infected with HIV. In the majority of these studies adefovir dipivoxil 10 mg was added to ongoing lamivudine treatment in patients failing lamivudine therapy.

In these clinical studies patients had active viral replication (HBV DNA ≥ 100,000 copies/ml) and elevated ALT levels (≥ 1.2 x Upper Limit of Normal (ULN)).

Experience in patients with compensated liver disease
In two placebo-controlled studies (total n=522) in HBeAg positive or in HBeAg negative chronic hepatitis B patients with compensated liver disease, significantly more patients (p < 0.001) in the 10 mg adefovir dipivoxil groups (53 and 64 %, respectively) had histological improvement from baseline at week 48 than in the placebo groups (25 and 33 %). Improvement was defined as a reduction from baseline of two points or more in the Knodell necro-inflammatory score with no concurrent worsening in the Knodell fibrosis score. Histological improvement was seen regardless of baseline demographic and hepatitis B characteristics, including prior interferon-alpha therapy. High baseline ALT levels (≥ 2 x ULN) and Knodell Histology Activity Index (HAI) scores (≥ 10) and low HBV DNA (< 7.6 log10 copies/ml) were associated with greater histological improvement. Blinded, ranked assessments of both necro-inflammatory activity and fibrosis at baseline and week 48, demonstrated that patients treated with 10 mg adefovir dipivoxil had improved necro-inflammatory and fibrosis scores relative to placebo-treated patients.

Assessment of the change in fibrosis after 48 weeks treatment using the Knodell scores confirms that patients treated with adefovir dipivoxil 10 mg had more regression and less progression of fibrosis than patients treated with placebo.

In the two studies mentioned above, treatment with 10 mg adefovir dipivoxil was associated with significant reductions in serum HBV DNA (3.52 and 3.91 log10 copies/ml, respectively, versus 0.55 and 1.35 log10 copies/ml), increased proportion of patients with normalisation of ALT (48 and 72 % versus 16 and 29 %) or increased proportion of patients with serum HBV DNA below the limits of quantification (< 400 copies/ml Roche Amplicor Monitor PCR assay) (21 and 51 % versus 0 %) when compared with placebo. In the study in HBeAg positive patients, HBeAg seroconversion (12 %) and HBeAg loss (24 %) was observed significantly more frequently in patients receiving 10 mg adefovir dipivoxil than in patients receiving placebo (6 % and 11 %, respectively) after 48 weeks of treatment.

In the HBeAg positive study, treatment beyond 48 weeks resulted in further reductions in serum HBV DNA levels and increases in the proportion of patients with ALT normalisation, HBeAg loss and seroconversion.

In the HBeAg negative study patients on adefovir dipivoxil (0-48 weeks) were re-randomised in a blinded-manner to continue on adefovir dipivoxil or receive placebo for an additional 48 weeks. At week 96, patients continuing on adefovir dipivoxil 10 mg had sustained suppression of serum HBV with maintenance of the reduction seen at week 48. In over two thirds of patients suppression of serum HBV DNA was associated with normalisation of ALT levels. In most patients who stopped treatment with adefovir dipivoxil, serum HBV DNA and ALT levels returned towards baseline.



Treatment with adefovir dipivoxil resulted in improvement in the liver fibrosis from baseline to 96 weeks therapy when analysed using the Ishak score (median change: Δ= -1). No differences in the median fibrosis score were seen between groups using the Knodell fibrosis score.

Patients who completed the first 96 weeks of the HBeAg negative study and received adefovir dipivoxil treatment during weeks 49 to 96, were offered the opportunity to receive open-label treatment with adefovir dipivoxil from study week 97 through to week 240. Serum HBV DNA levels remained undetectable and ALT levels normalised in approximately two thirds of patients following treatment with adefovir dipivoxil for up to 240 weeks. Clinically and statistically significant improvement in fibrosis was seen in the changes in Ishak scores from the start of adefovir dipivoxil treatment to the end of the study (week 240) (median change: Δ= -1).By the end of the study, 7 of 12 patients (58 %) with bridging fibrosis or cirrhosis at baseline, had an improved Ishak fibrosis score of ≥ 2 points. Five patients achieved and maintained HBsAg seroconversion (HBsAg negative/HBsAb positive).

Experience in patients pre- and post-liver transplantation with lamivudine-resistant HBV In a clinical study in 394 chronic hepatitis B patients with lamivudine-resistant HBV (pre-liver transplantation (n=186) and post-liver transplantation (n=208)), treatment with 10 mg adefovir dipivoxil resulted in a median reduction in serum HBV DNA of 4.1 and 4.2 log10 copies/ml, respectively, at week 48. In the pre-liver transplantation and post-liver transplantation cohorts 77 of 109 (71 %) patients and 64 of 159 (40 %) patients, respectively, achieved undetectable HBV DNA levels at week 48 (< 1,000 copies/ml Roche Amplicor Monitor PCR assay). Treatment with 10 mg adefovir dipivoxil showed similar efficacy regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. Improvements or stabilisation were seen in Child-Pugh- Turcotte score. Normalisation of ALT, albumin, bilirubin and prothrombin time was seen at week 48 in 51-85 % of the patients.

In the pre-liver transplantation cohort, 25 of 33 (76 %) patients achieved undetectable HBV DNA levels and 84 % of patients had ALT normalisation at 96 weeks. In the post-liver transplantation cohort, 61 of 94 (65 %) and 35 of 45 (78 %) of patients achieved undetectable HBV DNA levels at 96 and 144 weeks, respectively, and 70 % and 58 % of patients had ALT normalisation at these study visits. The clinical significance of these findings as they relate to histological improvement is not known.

Experience in patients with compensated liver disease and lamivudine-resistant HBV In a double-blind comparative study in chronic hepatitis B patients with lamivudine-resistant HBV (n=58), there was no median reduction in HBV DNA from baseline after 48 weeks of treatment with lamivudine. Forty-eight weeks of treatment with adefovir dipivoxil 10 mg alone or in combination with lamivudine resulted in a similar significant decrease in median serum HBV DNA levels from baseline (4.04 log10 copies/ml and 3.59 log10 copies/ml, respectively). The clinical significance of these observed changes in HBV DNA has not been established.

Experience in patients with decompensated liver disease and lamivudine-resistant HBV In 40 HBeAg positive or HBeAg negative patients with lamivudine-resistant HBV and decompensated liver disease receiving treatment with 100 mg lamivudine, addition of 10 mg adefovir dipivoxil treatment for 52 weeks resulted in a median reduction in HBV DNA of 4.6 log10 copies/ml.
Improvement in liver function was also seen after one year of therapy.

Experience in patients with HIV co-infection and lamivudine-resistant HBV In an open-label investigator study in 35 chronic hepatitis B patients with lamivudine-resistant HBV and co-infected with HIV, continued treatment with 10 mg adefovir dipivoxil resulted in progressive reductions in serum HBV DNA levels and ALT levels throughout the course of treatment up to 144 weeks.

In a second open-label, one-arm study, 10 mg adefovir dipivoxil and pegylated interferon alpha-2a were added to ongoing lamivudine therapy in 18 HIV/HBV co-infected patients with lamivudine-resistant HBV. Patients were all HBeAg positive and had median CD4 cell count of 

441 cells/mm3 (no patient had CD4 count < 200 cells/mm3). During therapy, serum HBV DNA levels were significantly lower compared to baseline for up to 48 weeks of treatment while ALT levels declined progressively from week 12. However, on-treatment HBV DNA response was not maintained off-therapy since all the patients had a rebound in HBV DNA after adefovir dipivoxil and pegylated interferon alpha-2a discontinuation. No patients became HBsAg- or HBeAg-negative during the study. Due to the small sample size and the study design, in particular the lack of treatment arms with pegylated interferon alpha-2a monotherapy and with adefovir monotherapy, it is not possible to draw formal conclusions on the best therapeutic management of HIV co-infected patients with lamivudine-resistant HBV.

Clinical resistance in patients receiving adefovir dipivoxil as monotherapy and in combination with lamivudine
In several clinical studies (HBeAg positive, HBeAg negative, pre- and post-liver transplantation with lamivudine-resistant HBV and lamivudine-resistant HBV co-infected with HIV patients), genotypic analyses were conducted on HBV isolates from 379 of a total of 629 patients, treated with adefovir dipivoxil for 48 weeks. No HBV DNA polymerase mutations associated with resistance to adefovir were identified when patients were genotyped at baseline and at week 48. After 96, 144, 192 and 240 weeks of treatment with adefovir dipivoxil, resistance surveillance was performed for 293, 221,
116 and 64 patients, respectively. Two novel conserved site mutations were identified in the HBV polymerase gene (rtN236T and rtA181V), which conferred clinical resistance to adefovir dipivoxil.
The cumulative probabilities of developing these adefovir-associated resistance mutations in all patients treated with adefovir dipivoxil were 0 % at 48 weeks and approximately 2 %, 7 %, 14 % and 25 % after 96, 144, 192 and 240 weeks, respectively.

Clinical resistance in monotherapy studies in nucleoside naïve patients In patients receiving adefovir dipivoxil monotherapy (HBeAg negative study) the cumulative probability of developing adefovir-associated resistance mutations was 0 %, 3 %, 11 %, 18 % and 29 % at 48, 96, 144, 192 and 240 weeks respectively. 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 (< 1,000 copies/ml) at week 48 as compared to patients with serum HBV DNA above 1,000 copies/ml at week 48. In HBeAg positive patients, the incidence of adefovir-associated resistance mutations was 3 % (2/65), 17 % (11/65) and 20 % (13/65) after a median duration exposure of 135, 189 and 235 weeks respectively.

Clinical resistance in studies where adefovir dipivoxil was added to ongoing lamivudine in patients with lamivudine-resistance
In an open-label study of pre- and post-liver transplantation patients with clinical evidence of lamivudine-resistant HBV, no adefovir-associated resistance mutations were observed at week 48.
With up to 3 years of exposure, no patients receiving both adefovir dipivoxil and lamivudine developed resistance to adefovir dipivoxil. However, 4 patients who discontinued lamivudine treatment developed the rtN236T mutation while receiving adefovir dipivoxil monotherapy and all experienced serum HBV rebound.

The currently available data both in vitro and in patients suggest that HBV expressing the adefovir- associated resistance mutation rtN236T is susceptible to lamivudine. Preliminary clinical data suggest the adefovir-associated resistance mutation rtA181V may confer a reduced susceptibility to lamivudine, and the lamivudine-associated mutation rtA181T may confer a reduced susceptibility to adefovir dipivoxil.

Paediatric population
The efficacy and safety of a daily dose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (aged from 2 to < 18 years) were examined in a double-blind, randomised, placebo-controlled study in 173 paediatric patients (115 on adefovir dipivoxil, 58 on placebo) who had HBeAg positive chronic hepatitis B, serum ALT levels ≥ 1.5 x upper limit of normal (ULN) and compensated liver disease. At week 48, in children aged 2 to 11 years old, no statistically significant difference was observed in the proportions of patients that achieved the primary endpoint of serum HBV DNA < 1,000 copies/ml and normal ALT levels between the placebo arm and the adefovir dipivoxil arm. In the adolescent 
population (n=83) (aged from 12 to < 18 years), significantly more patients treated with adefovir dipivoxil achieved the primary efficacy endpoint and obtained significant reductions in serum HBV DNA (23 %) compared to placebo-treated patients (0 %). However, the proportions of subjects who achieved HBeAg seroconversion at week 48 were similar (11 %) between the placebo arm and the adefovir dipivoxil 10 mg arm in adolescent patients.

Overall, the safety profile of adefovir dipivoxil in children was consistent with the known safety profile in adult patients. However, a signal towards a higher rate of decreased appetite and/or food intake was observed in the adefovir arm as compared to the placebo arm. At week 48 and 96, mean changes from baseline in weight and BMI Z scores tended to decrease in adefovir dipivoxil-treated patients. At week 48, all placebo-treated subjects who did not exhibit HBeAg or HBsAg seroconversion, plus all adefovir dipivoxil-treated subjects, were offered the opportunity to receive open-label adefovir dipivoxil from study week 49 through to week 240. A high rate (30%) of hepatic flares was reported following discontinuation of adefovir dipivoxil during the 3 years open-label phase of the study. Furthermore, for the few patients who remained on drug at week 240 (n=12) BMI Z score was lower than typical for their age and gender. Very few patients developed adefovir-associated mutations up to 5 years; however, the number of patients who remained on drugs above week 96 was limited. Due to their limitations, the clinical data available do not allow to draw definitive conclusions on the benefit/risk ratio of the adefovir treatment in children with chronic hepatitis B (see section 4.2).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active substance adefovir, an acyclic nucleotide analogue which is actively transported into cells where it is converted by host enzymes to adefovir diphosphate.

Absorption
The oral bioavailability of adefovir from 10 mg adefovir dipivoxil is 59 %. Following oral administration of a single dose of 10 mg adefovir dipivoxil to chronic hepatitis B patients, the median (range) peak serum concentration (Cmax) was achieved after 1.75 h (0.58-4.0 h). Median Cmax and AUC0-∞ values were 16.70 (9.66-30.56) ng/ml and 204.40 (109.75-356.05) ng·h/ml, respectively.
Systemic exposure to adefovir was not affected when 10 mg adefovir dipivoxil was taken with a high fat meal. The tmax was delayed by two hours.

Distribution
Preclinical studies show that after oral administration of adefovir dipivoxil, adefovir is distributed to most tissues with the highest concentrations occurring in kidney, liver and intestinal tissues. In vitro binding of adefovir to human plasma or human serum proteins is ≤ 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.

Biotransformation
Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. At concentrations substantially higher (> 4,000-fold) than those observed in vivo, adefovir did not inhibit any of the following human CYP450 isoforms, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4. Based on the results of these in vitro experiments and the known elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir with other medicinal products is low.

Elimination
Adefovir is excreted renally by a combination of glomerular filtration and active tubular secretion. The median (min-max) renal clearance of adefovir in subjects with normal renal function (Clcr > 80 ml/min) is 211 ml/min (172-316 ml/min), approximately twice calculated creatinine clearance (Cockroft-Gault method). After repeated administration of 10 mg adefovir dipivoxil, 45 % of the dose is recovered as adefovir in the urine over 24 hours. Plasma adefovir concentrations declined in a biexponential manner with a median terminal elimination half-life of 7.22 h (4.72-10.70 h).


Linearity/non-linearity
The pharmacokinetics of adefovir are proportional to dose when given as adefovir dipivoxil over the dose range of 10 to 60 mg. Repeated dosing of adefovir dipivoxil 10 mg daily did not influence the pharmacokinetics of adefovir.

Pharmacokinetic/pharmacodynamic relationship(s)

Gender, age and ethnicity
The pharmacokinetics of adefovir were similar in male and female patients. Pharmacokinetic studies have not been conducted in the elderly. Pharmacokinetic studies were principally conducted in Caucasian patients. The available data do not appear to indicate any difference in pharmacokinetics with regard to race.

Renal impairment
The mean (± SD) pharmacokinetic parameters of adefovir following administration of a single dose of 10 mg adefovir dipivoxil to patients with varying degrees of renal impairment are described in the table below:

Renal Function Group                  Unimpaired                    Mild         Moderate        Severe Baseline Creatinine                       > 80                     50-80           30-49          10-29 Clearance (ml/min)                       (n=7)                     (n=8)           (n=7)         (n=10) Cmax (ng/ml)                           17.8±3.2                   22.4±4.0        28.5±8.6      51.6±10.3 AUC0-∞ (ng·h/ml)                       201±40.8                   266±55.7       455±176        1240±629 CL/F (ml/min)                          469±99.0                   356±85.6       237±118        91.7±51.3 CLrenal (ml/min)                       231±48.9                   148±39.3       83.9±27.5      37.0±18.4 
A four-hour period of haemodialysis removed approximately 35 % of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.

It is recommended that the dosing interval of 10 mg adefovir dipivoxil is modified in patients with creatinine clearance between 30 and 49 ml/min. Adefovir dipivoxil is not recommended in patients with creatinine clearance of < 30 ml/min or in patients on dialysis (see section 4.2 and 4.4).

Hepatic impairment
Pharmacokinetic properties were similar in patients with moderate and severe hepatic impairment compared to healthy volunteers (see section 4.2).

Paediatric population
The pharmacokinetics of adefovir dipivoxil were studied in an efficacy and safety study of a daily dose of 0.25 mg/kg to 10 mg adefovir dipivoxil in children (aged 2 to < 18 years). Pharmacokinetic analysis revealed that adefovir exposure was comparable among 3 age groups, 2 to 6 years (0.3 mg/kg), 7 to 11 years (0.25 mg/kg) and 12 to 17 years (10 mg) and all age groups achieved adefovir exposure in the target range (for efficacy results see section 5.1), which was based on adefovir plasma concentrations in adult patients with chronic hepatitis B with established safety and efficacy profiles.