Dolutegravir

Dolutegravir (GSK1349572) is a potent, next-generation HIV integrase (IN) inhibitor, inhibits HIV-1 integrase-catalyzed strand transfer with IC50 of 2.7 nM; inhibits HIV-1 replication in PBMCs, MT-4 cells and in the PHIV assay with EC50 of 0.51, 0.71 and 2.2 nM, respectively; demonstrates activity against site-directed molecular clones containing the raltegravir-resistant signature mutations Y143R, Q148K, N155H, and G140S/Q148H; exhibits excellent anti-HIV activity in combination with representative approved antiretroviral agents in vivo.HIV Infection Approved (In Vitro) :The EC50 of Dolutegravir (S/GSK1349572) against HIV-1 is 0.51 nM in PBMCs, 0.71 nM in MT-4 cells, and 2.2 nM in the PHIV assay, which uses a pseudotyped self-inactivating virus. The 50% cytotoxic concentrations (CC50) for Dolutegravir in proliferating IM-9, U-937, MT-4, and Molt-4 cells are 4.8, 7.0, 14, and 15 μM, respectively. In unstimulated and stimulated PBMCs, the CC50 are 189 μM and 52 μM, respectively. Based on the EC50 of Dolutegravir against HIV-1 in PBMCs (i.e., 0.51 nM), this translates to a cell-based therapeutic index of at least 9,400. (In Vivo) :Following a single intravenous (IV) administration of Dolutegravir, the plasma clearance is low in rats (0.23 mL/min/kg) and monkeys (2.12 mL/min/kg) . The half-lives in the rat and monkey are similar, approximately 6 h, and the steady-state volume of distribution (VSS) is low. Following oral administration, Dolutegravir is rapidly absorbed with a high oral bioavailability when administered as a solution to fasted male rats and a single monkey (75.6 and 87.0%, respectively) . Dolutegravir exposure (Cmax and AUC) increased with increasing dose following oral administration of 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.