| Indication |
For use, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. |
| Pharmacodynamics |
Tenofovir belongs to a class of antiretroviral drugs known as
nucleotide analogue reverse transcriptase inhibitors (NtRTIs), which
block reverse transcriptase, an enzyme crucial to viral production in
HIV-infected people. Tenofovir is currently in late-stage clinical
trials for the treatment of hepatitis B. Tenofovir disoproxil fumarate
is an acyclic nucleoside phosphonate diester analog of adenosine
monophosphate. Tenofovir requires initial diester hydrolysis for
conversion to tenofovir and subsequent phosphorylations by cellular
enzymes to form tenofovir diphosphate. Tenofovir diphosphate is a weak
inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA
polymerase γ. |
| Mechanism of action |
Tenofovir inhibits the activity of HIV reverse transcriptase by
competing with the natural substrate deoxyadenosine 5’-triphosphate and,
after incorporation into DNA, by DNA chain termination. Specifically,
the drugs are analogues of the naturally occurring deoxynucleotides
needed to synthesize the viral DNA and they compete with the natural
deoxynucleotides for incorporation into the growing viral DNA chain.
However, unlike the natural deoxynucleotides substrates, NRTIs and
NtRTIs (nucleoside/tide reverse transcriptase inhibitors) lack a
3'-hydroxyl group on the deoxyribose moiety. As a result, following
incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide
cannot form the next 5'-3' phosphodiester bond needed to extend the DNA
chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis
is halted, a process known as chain termination. All NRTIs and NtRTIs
are classified as competitive substrate inhibitors. |
| Absorption |
The oral bioavailability in fasted patients is approximately 25%.
Administration of food (high fat meal containing 40 to 50% fat)
increases the oral bioavailability, with an increase in the AUC of
approximately 40%. |
| Volume of distribution |
- 1.3 ± 0.6 L/kg [tenofovir 1.0 mg/kg]
- 1.2 ± 0.4 L/kg [tenofovir 3.0 mg/kg]
|
| Protein binding |
Very low: < 0.7% to human plasma proteins and < 7.2% to serum proteins |
| Metabolism |
Neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. |
| Route of elimination |
Not Available |
| Half life |
Approximately 17 hours. |
| Clearance |
Not Available |
| Toxicity |
Limited clinical experience at doses higher than the therapeutic
dose of tenofovir 300 mg is available. In Study 901 tenofovir disoproxil
fumarate 600 mg was administered to 8 patients orally for 28 days. No
severe adverse reactions were reported. The effects of higher doses are
not known. |
