Product Name

Tenofovir Alafenamide

CAS Number

379270-37-8

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Product Name:

Tenofovir Alafenamide

CAS Number:

379270-37-8

Indication:

Tenofovir alafenamide is indicated for the treatment of chronic hepatitis B in adult patients with compensated liver disease.9 In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg.11 This combination is also indicated to prevent HIV-1 infections in high risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex.11,17 When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg.11 In the combination product with emtricitabine and bictegravir, tenofovir alafenamide is considered as a complete regimen for the treatment of HIV-1 infection in treatment-naive patients or in patients virologically suppressed for at least 3 months with no history of treatment failure.12 Additionally, the combination product including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the combination product including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure.13 The combination product including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir.

Mode of Action:

Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil.2 This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate.5

Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells.5

Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis.9 To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir.

Pharmacodynamics:

Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication.4

Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir.1

In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil

Metabolism:

To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells.1

After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid.

Toxicity:

The LD50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%.15

Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility.

IUPAC:

propan-2-yl (2S)-2-{[(S)-({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)(phenoxy)phosphoryl]amino}propanoate

DrugBank:

DB09299

Formula:

C21-H29-N6-O5-P

SMILES:

CC(C)OC(=O)[C@H](C)N[P@](=O)(CO[C@H](C)CN1C=NC2=C(N)N=CN=C12)OC1=CC=CC=C1

InChi:

InChI=1S/C21H29N6O5P/c1-14(2)31-21(28)16(4)26-33(29,32-17-8-6-5-7-9-17)13-30-15(3)10-27-12-25-18-19(22)23-11-24-20(18)27/h5-9,11-12,14-16H,10,13H2,1-4H3,(H,26,29)(H2,22,23,24)/t15-,16+,33+/m1/s1

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Tenofovir Alafenamide

379270-37-8

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