New boosting alternatives to ritonavir: GS-99350 and SPI-452

GS-9350 is a potent CYP3A inhibitor currently in development by Gilead Sciences.

This oral presentation described the safety, tolerability and pharmacokinetics of GS-9350 and compared its effect on midazolam with that of ritonavir. [1]

The two key goals in the development programme were i) to maintain the potent mechanism based inhibition that ritonavir has on CYP3A and ii) to remove anti-HIV activity from the booster. In the laboratory screen there was greater specificity for inhibition of CYP3A versus some other CYP enzymes than ritonavir. Also there was less induction potential through activation of nuclear receptors than ritonavir and reduced potential for lipid abnormalities as assessed by in vitro adipocyte function tests.

Importantly the physiochemical properties of the molecule allow formulation as a solid dosage form. In the initial clinical studies GS-9350 was generally well tolerated and there was no evidence of PR or QTc prolongation. GS-9350 demonstrated non-linear pharmacokinetics and doses of 100 or 200 mg exhibited a similar inhibition effect on midazolam apparent clearance as that of ritonavir 100 mg (92%, 95% and 95%, respectively).

Based on these data a quad tablet containing tenofovir + emtricitabine + elvitegravir + GS-9350 will go forward to further study.

Sequoia Pharmaceuticals are developing SPI-452, a potent and selective inhibitor of CYP3A that also lacks antiviral activity. [2]

Its tolerability, pharmacokinetics and ability to booster darunavir and atazanavir were evaluated in healthy volunteers. When dosed up to 200 mg once daily for 15 days, SPI-452 was well tolerated and safe, with no serious adverse events. There were no significant changes in triglycerides or LDL cholesterol. Trough concentrations of darunavir were increased by 29-fold and those of atazanavir increased by 13-fold.