Tenofovir disoproxil fumarate (TDF) is an oral prodrug of tenofovir (TFV), a nucleotide analog mimicking deoxyadenosine monophosphate, and is one of the most widely prescribed drugs for the treatment of HIV infection. In 2011, over 3 million HIV infected patients globally were treated with a TDF-containing regimen. A new amidate prodrug of TFV, GS-7340, is currently in Phase 2 clinical development. This drug has a unique pharmacokinetic profile that preferentially targets cells and tissues involved in HIV replication (PBMCs and lymphoid organs) and is > 100 fold more potent in vitro than parent TFV. Administration of GS-7340 results in high concentrations of tenofovir diphosphate (TFV-DP), the active inhibitor of HIV replication, in PBMCs and substantially reduced levels of circulating TFV, providing less exposure to kidney and bone, and hopefully resulting in fewer of the side effects which are infrequently associated with the use of TDF. At a dose of 25 mg/day, GS-7340 provides 7 times the concentration of TFV-DP in PBMCs, but less than 10% of the plasma levels of TFV, compared with a standard daily dose of 300 mg TDF. The high potency of GS-7340 results in significantly greater antiretroviral activity, a potentially more favorable resistance profile, and a much lower daily dosage, allowing for novel co-formulations, including a single tablet regimen with a boosted HIV protease inhibitor. The lower daily dose may also allow for significant reductions in the pricing of tenofovir containing regimens for the developing world. Another formulation of tenofovir, CMX157 (hexadecyloxylpropyl tenofovir), is a lipid conjugated form of tenofovir currently in phase 2 clinical development. This formulation also provides for lower circulating levels of tenofovir than TDF with the current doses being tested. Another compound in early development is GS-9131, an amidate prodrug of an adenosine nucleotide analog with a dihydrofuran core, and a unique resistance profile with potent activity against most viruses that are resistant to currently available nucleoside analog reverse transcriptase inhibitors of HIV.
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