Dolutegravir sodium is an HIV integrase inhibitor (IC50= 2.7 nM) with modest activity against raltegravir-resistant signature mutants Y143R, Q148K, N155H, and G140S/Q148H.
Dolutegravir sodium (S/GSK1349572 sodium) is a potent, orally available inhibitor of HIV integrase strand transfer, exhibiting an IC50 of 2.7 nM against HIV-1 integrase-mediated strand transfer. It effectively suppresses HIV-1 viral replication with an IC50 of 0.51 nM in peripheral blood mononuclear cells. Dolutegravir sodium also maintains high efficacy against HIV-1 mutants Y143R, N155H, and G140S/Q148H, with EC50 values ranging from 3.6 to 5.8 nM[1][2]. Dolutegravir (S/GSK1349572) exhibits an EC50 against HIV-1 of 0.51 nM in PBMCs, 0.71 nM in MT-4 cells, and 2.2 nM in the PHIV assay using a pseudotyped self-inactivating virus. The 50% cytotoxic concentrations (CC50) of Dolutegravir in various cells, such as proliferating IM-9, U-937, MT-4, and Molt-4, are 4.8, 7.0, 14, and 15 μM respectively. In unstimulated and stimulated PBMCs, CC50 values are 189 μM and 52 μM, respectively. Given the EC50 of Dolutegravir against HIV-1 in PBMCs (0.51 nM), the calculated cell-based therapeutic index is at least 9,400[1].
Dolutegravir sodium 动物研究
Animal study
After a single intravenous (IV) administration, Dolutegravir shows low plasma clearance in rats (0.23 mL/min/kg) and monkeys (2.12 mL/min/kg). Both species exhibit similar half-lives of approximately 6 hours, and the steady-state volume of distribution (VSS) is low. Following oral administration, Dolutegravir is rapidly absorbed with high oral bioavailability when given as a solution to fasted male rats and a single monkey (75.6% and 87.0%, respectively). The exposure to Dolutegravir (Cmax and AUC) increases with rising doses when administered orally as a suspension to non-fasted rats up to 250 mg/kg and non-fasted monkeys up to 50 mg/kg, although the increase is less than proportional[2].
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