Background: HIV protease inhibitors (PIs) represent an important antiretroviral class largely due to their low potential to select for clinical resistance. Despite extensive discovery and development efforts over the past 30 years, all marketed PIs suffer from high rates of hepatic oxidative metabolism, leaving none that are suitable for once-daily (QD) dosing without pharmacokinetic boosting. Here we describe a novel, potent HIV PI that exhibits a high resistance barrier, exceptional metabolic stability, and has the potential for use as an unboosted, QD oral agent for the treatment of HIV infection.
Methods: Antiretroviral EC[sub]50[/sub] and Hill-coefficient values were measured in a cytopathic MT4 T-cell assay. PI cross-resistance was assessed against a panel of atazanavir (ATV) and darunavir (DRV) resistance-associated HIV-1 mutants (RAMs). Predicted drug clearance (CL) was measured in human liver microsomes with added cofactors. Oral and intravenous pharmacokinetic studies were conducted in rat and dog.
Results: GS-PI1 is a potent inhibitor of HIV replication in MT4 cells with an EC50 of 4.9 nM (ATV and DRV EC50 values are 10.7 and 7.5 nM, respectively), a Hill-slope of 5.0, and a protein-adjusted EC95 of 310 nM. Similar antiretroviral potency was observed in PBMCs. GS-PI1 potency was reduced <2-fold against major PI RAMs, whereas ATV and DRV potency shifts are as high as 56 and 35-fold, respectively. GS-PI1 retains a high barrier to resistance emergence in vitro, as evidenced by the lack of viral breakthrough in HIV-infected MT2 cells at a fixed drug concentration equal to 2x its EC50. GS-PI1 has oral bioavailabilities of 37% and 18%, and half-lives of 13 and 14 hours in rat and dog respectively. The in vivo half-lives of GS-PI1 are 10 to 40-fold longer than those of ATV (0.37 h rat, 1.3 h dog) or DRV (0.32 h rat, 0.34 h dog). The human predicted clearance (CL) for GS-PI1 is 0.05 L/h/kg (4% hepatic extraction) compared to predicted CLs of 1.20 and 1.07 L/h/kg for DRV and ATV (92% and 83% hepatic extraction), respectively.
Conclusion: GS-PI1 represents a new class of HIV protease inhibitor possessing favorable potency, resistance barrier, and in vivo half-lives relative to marketed HIV PIs and has been designed to achieve metabolic stability without pharmacokinetic boosting. GS-PI1 has the potential for once-daily oral dosing without boosting in the treatment of HIV infection.