Description
Tenofovir is an analog of adenosine monophosphate that has antiviral activity.
1,2 It is converted by cellular enzymes to tenofovir diphosphate, an obligate chain terminator that inhibits the activity of HIV reverse transcriptase and hepatitis B virus polymerase.
3,4 Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α and β and mitochondrial DNA polymerase γ.
4 For
in vivo and cell culture use, tenofovir is supplied as a water soluble prodrug in the form of tenofovir disoproxil (fumarate) (Item No.
16922), which increases the intracellular diphosphorylated compound >1,000-
fold above the level attained with unmodified tenofovir.
4
Chemical Properties
White Crystalline Solid
Definition
ChEBI: A member of the class of phosphonic acids that is methylphosphonic acid in which one of the methyl hydrogens is replaced by a [(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy group. An inhibitor of HIV-1 reverse transcriptase, the bis(isopropyloxycarbonyloxy
ethyl) ester (disoproxil ester) prodrug is used as the fumaric acid salt in combination therapy for the treatment of HIV infection.
Indications
Tenofovir disoproxil fumarate (Viread) is a prodrug of
tenofovir, a phosphorylated adenosine nucleoside analogue,
and is the only available agent of its class. It is
converted by cellular enzymes to tenofovir diphosphate,
which competes with deoxyadenosine triphosphate
(dATP) for access to reverse transcriptase and
causes chain termination following its incorporation.
Tenofovir was approved as part of a combination therapy
for HIV in adults who failed treatment with other
regimens; it appears to be effective against HIV strains
that are resistant to NRTIs.
Acquired resistance
HIV variants with the K65R mutation and the K70E mutation
in the reverse transcriptase demonstrate reduced susceptibility
to tenofovir.
Pharmaceutical Applications
A nucleotide analog structurally similar to adefovir.
EC50 values for HBV, assessed in the HepG2 2.2.15 cell
line, ranged from 0.14 to 1.5 μm; the cytotoxic concentration
exceeded 100 μm. A decline in HBV DNA levels below
105 copies/mL at 48 weeks of therapy in 100% of patients
receiving tenofovir compared with 44% on adefovir therapy
has been reported. There are also case reports of patients with
primary resistance to adefovir responding to tenofovir.
It is generally well tolerated in patients with chronic HBV;
the most common side effects include nausea and gastrointestinal
upset, headache, dizziness, fatigue and rash.
Pharmaceutical Applications
An acyclic nucleoside phosphonate, formulated as the disoproxil
fumarate salt for oral administration.
Biological Activity
Selectively inhibits HIV reverse transcriptase (RNA-dependent DNA polymerase). Prevents cytotoxicity in SIV-infected C-8166 cells in vitro (IC 50 = 1.5 μ M). Antiviral agent.
Biochem/physiol Actions
Tenofovir has a low oral bioavailability. Hence, it is available as a prodrug called tenofovir disoproxil fumarate. Once ingested, tenofovir disoproxil fumarate is hydrolyzed to tenofovir and phosphorylated. This is then incorporated into the viral DNA which leads to chain termination. Tenofovir is also effective against hepatitis B virus.
Clinical Use
Chronic hepatitis B infection
Clinical Use
Treatment of HIV infection in adults and children (in combination with
other antiretroviral drugs)
Side effects
In clinical trials of antiretroviral treatment-naive participants,
the most commonly reported adverse events were mild to
moderate gastrointestinal upset (nausea 8%, diarrhea 11%),
headache (14%) and depression (11%). Tenofovir has the
potential to result in nephrotoxicity, particularly through proximal
tubular damage, but the risk of clinically significant renal
dysfunction appears relatively low and seems to occur mainly
in subjects with other identifiable risks for renal impairment.
Minor elevations in serum creatinine and reductions in creatinine
clearance occur, but rarely require drug discontinuation.
A few (<0.1%) cases of osteomalacia and decreased bone
density have been reported.
Side effects
Tenofovir is taken once daily and is generally well
tolerated, perhaps because it produces less mitochondrial
toxicity than the NRTIs. Nausea, vomiting, flatulence,
and diarrhea occur in 10% or fewer patients.
Resistance to tenofovir has been documented, and
cross-resistance to NRTIs may occur.
