›IDX899, an Aryl Phosphinate-Indole Non-Nucleoside Reverse Transcriptase Inhibitor for the Potential Treatment of HIV Infection
Curr Opin Investig Drugs. 2010 Feb;11(2):237-45. Klibanov OM, Kaczor RL. Wingate University School of Pharmacy, Wingate, NC 28174-0159, USA.
Antiretroviral drug resistance is one of the complications of highly active antiretroviral therapy (HAART). Second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are being developed for use in patients infected with HIV-1 because of the enhanced activity of these inhibitors against viruses that are resistant to the first-generation NNRTIs[i.e. resistant to Sustiva].
IDX899 (GSK-2248761), under development by Idenix Pharmaceuticals Inc and ViiV Healthcare[ViiV is the GSK/PE JV for HIV development: #msg-43254006], is an aryl phosphinate-indole second-generation NNRTI that potently and selectively inhibits wild-type and NNRTI-resistant HIV-1 in vitro. Preclinical data for IDX899 suggest a significantly greater barrier to resistance compared with that of the first-generation NNRTI efavirenz[Sustiva]. Two pathways of resistance have been identified for IDX899 in vitro that include Glu138Lys and Val90Ile/Tyr181Cys mutations.
Pharmacokinetic studies demonstrated that IDX899 exhibits linear, dose-proportional and food-dependent pharmacokinetics[hence the PK/food study currently being conducted by GSK: #msg-44790049]; Cmin concentrations achieved with this drug allow once-daily dosing. In phase I clinical trials, IDX899 reduced HIV-1 RNA and increased CD4+ cell counts in treatment-naïve patients infected with HIV-1. At the time of publication, a phase II clinical trial of IDX899 was being conducted.‹
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