Pharmacology: Pharmacodynamics: 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 deoxyribonucleic acid (DNA), causes DNA chain termination. 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 (t½
) of 12-36 hrs in activated and resting lymphocytes.
Adefovir is active against hepadnaviruses in vitro
, including all common forms of lamivudine-resistant hepatitis B virus (HBV) (L528M, M552I, M552V, L528M/M552V), famciclovir-associated mutations (V521L, P525L, L528M, T532S or V555I) and hepatitis B immunoglobulin escape mutations (T476N and W501Q), and in in vivo
animal models of HBV.
Two (2) mutations (rtN236T and rtA181V) in the HBV reverse transcriptase domain have been shown to be associated with resistance to adefovir.
, the rtN236T mutation conferred a 4- to 14-fold reduced susceptibility and the rtA181V mutation conferred a 2.5- to 4.2-fold reduced susceptibility to adefovir.
, the rtN236T mutation conferred a 2- to 3-fold reduced susceptibility to lamivudine and the rtA181V mutation conferred a 1- to 14-fold reduced susceptibility to lamivudine.
Resistance to adefovir dipivoxil can result in viral load rebound which may result in exacerbation of hepatitis B and in the setting of diminished hepatic function, lead to liver decompensation, and possible fatal outcome.
In patients with evidence of lamivudine resistance (rtL180M, rtA181T, and/or rtM2041/V) or with prior lamivudine exposure, adefovir dipivoxil should be used in combination with lamivudine and not as adefovir dipivoxil monotherapy in order to reduce the risk of resistance to adefovir.
In order to reduce the risk of resistance in patients receiving adefovir dipivoxil monotherapy, a modification of treatment should be considered if serum HBV DNA remains >1,000 copies/mL.
Adefovir dipivoxil is a dipivaloyloxymethyl ester prodrug of the active ingredient adefovir. The oral bioavailability of adefovir from Hepsera 10 mg is 59%. Following oral administration of a single dose of Hepsera 10 mg to chronic hepatitis B patients, the median (range) peak serum concentration (Cmax
) was achieved after 1.75 hrs (0.58-4 hrs). Median Cmax
values were 16.7 (9.66-30.56) ng/mL and 204.4 (109.75-356.05) ng·hr/mL, respectively. Co-administration of Hepsera 10 mg with food did not affect systemic exposure to adefovir.
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%, respectively, over the adefovir concentration range of 0.1-25 mcg/mL. The volume of distribution at steady state following IV administration of 1 or 3 mg/kg/day is 392±75 and 352±9 mL/kg, respectively.
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. Adefovir is not a substrate for these enzymes. 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.
Adefovir is excreted renally by a combination of glomerular filtration and active tubular secretion. After repeated administration of Hepsera 10 mg, 45% of the dose is recovered as adefovir in the urine over 24 hrs. Plasma adefovir concentrations declined in a biexponential manner with a median terminal elimination t½
of 7.22 hrs (4.72-10.7 hrs).
The pharmacokinetics of adefovir are proportional to dose over an adefovir dipivoxil dose range of 10-60 mg and are not influenced by repeat dosing.
Special Patient Populations: Gender:
The pharmacokinetics of adefovir were similar in male and female patients.
Pharmacokinetic studies have not been conducted in the elderly.
Pharmacokinetic studies have not been conducted in children.
The available data do not appear to indicate any difference in pharmacokinetics with regard to race.
In patients with moderately or severely impaired renal function or with end-stage renal disease (ESRD) requiring dialysis, Cmax
of adefovir were increased. It is recommended that the dosing interval of Hepsera 10 mg is modified in patients with creatinine clearance (CrCl) <50 mL/min or in patients who already have ESRD and require dialysis (see Dosage & Administration).
The mean (+SD) pharmacokinetic parameters of adefovir following administration of a single dose of Hepsera 10 mg to patients with varying degrees of renal impairment are described in Table 1. (See Table 1.)
Click on icon to see table/diagram/image
A 4-hr period of haemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.
Pharmacokinetic properties were similar in patients with moderate and severe hepatic impairment compared to healthy volunteers (see Dosage & Administration).
Clinical Data: Emergence of Adefovir-Resistant HBV During Clinical Studies: Monotherapy:
In placebo-controlled phase 3 clinical trials, genotypic and phenotypic analyses were conducted on HBV isolates from 271 patients with HBeAg-positive or presumed precore mutant chronic hepatitis B, treated with Hepsera 10 mg 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.
In HBeAg-negative patients, the cumulative probability of adefovir-associated resistance mutations was 3%, 11%, 18% and 29% at 96, 144, 192 and 240 weeks, respectively. In HBeAg-positive patients, the incidence of adefovir-associated resistance mutations was 3%, 17% and 20% after a median duration exposure of 135, 189 and 235 weeks, respectively.
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 Hepsera and lamivudine developed resistance to Hepsera. However, 4 patients who discontinued lamivudine treatment developed the rtN236T mutation while receiving Hepsera monotherapy, and all experienced serum HBV rebound.
Toxicology: Preclinical Safety Data:
The primary dose-limiting toxic effect associated with administration of Hepsera in animals (mice, rats and monkeys) was renal tubular nephropathy characterised by histological alterations and/or increases in blood urea nitrogen and serum creatinine. Nephrotoxicity was observed in animals at systemic exposures at least 3-10 times higher than those achieved in humans at the recommended therapeutic dose of 10 mg/day.
No effects on male or female fertility, or reproductive performance, occurred in rats and there was no embryotoxicity or teratogenicity in rats or rabbits administered with Hepsera orally.
When Hepsera was administered IV to pregnant rats at doses associated with notable maternal toxicity (20 mg/kg/day, systemic exposure approximately 38 times that achieved in humans at the therapeutic dose), embryotoxicity and an increased incidence of foetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) were observed. No adverse effects on development were seen at 2.5 mg/kg/day administered IV (systemic exposure approximately 12 times that achieved in humans at the therapeutic dose).
Hepsera was mutagenic in the in vitro
mouse lymphoma cell assay (with or without metabolic activation), but was not clastogenic in the in vivo
mouse micronucleus assay at doses up to 2,000 mg/kg.
Hepsera was not mutagenic in microbial mutagenicity assays involving Salmonella typhimurium
(Ames) and Escherichia coli
in the presence and absence of metabolic activation. Adefovir-induced chromosomal aberrations in the in vitro
human peripheral blood lymphocyte assay without metabolic activation.
In long-term carcinogenicity studies in rats and mice with Hepsera, no treatment-related increase in tumour incidence was found in mice at 10 mg/kg/day or in rats at 5 mg/kg/day (systemic exposures approximately 10 and 4 times those achieved in man at the therapeutic dose of 10 mg/day, respectively).