Gilead, the manufacturer of two of the biggest-selling HIV drugs in the world, tenofovir and emtricitabine, has announced that it has begun human studies of a product that could replace ritonavir as an antiretroviral boosting agent in some fixed-dose combinations.
GS 9350, as the product is known, is a once-daily, heat-stable compound that can be coformulated with other agents including tenofovir and Gilead’s integrase inhibitor elvitegravir (which must currently be boosted with ritonavir to maintain high blood levels).
GS 9350 is currently being tested in a Phase I single and multiple dose-ranging clinical study. The study is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of escalating single and multiple doses of GS 9350 in healthy volunteers.
Ritonavir (Norvir), a protease inhibitor manufactured by Abbott, has an extraordinary capacity to boost blood levels of most antiretroviral drugs processed through a metabolic system called cytochrome p450 which governs the metabolism of many compounds in the body (including a host of medicines).
Ritonavir boosts drug levels by slowing down processing through this pathway, causing higher levels of drug to build up in the body. Ritonavir is the most potent known inhibitor of cytochrome p450 CYP 3A4, the route through which protease inhibitors are metabolised.
All currently prescibed protease inhibitors apart from nelfinavir (Viracept) are usually boosted with a low dose of ritonavir, and Abbott’s protease inhibitor lopinavir is coformulated with a low dose of ritonavir in the product Kaletra.
However, there are drawbacks to ritonavir use as a boosting agent. Ritonavir causes increases in triglyceride levels even at very low doses, which must sometimes be controlled with medication or even result in switches to other drugs. It may also have a role in the gastrointestinal problems such as diarrhoea, flatulence and nausea experienced by some patients taking protease inhibitors.
Ritonavir is also viewed as a problem by pharmaceutical companies because it is owned by Abbott, which raised the price of the drug fivefold in December 2003 in order to make its coformulated product Kaletra more attractive than competing protease inhibitors that relied on ritonavir boosting.
Abbott’s ownership of ritonavir makes it impossible for competitors to coformulate their products with ritonavir.
Gilead’s aim is to coformulate GS 9350 in a single tablet with its investigational integrase inhibitor elvitegravir, tenofovir and emtricitabine. The company says that preliminary studies have shown this is possible.
Coformulation deals with other companies could follow, with Bristol Myers-Squibb’s atazananvir (Reyataz) an obvious candidate. A second or third-line fixed dose product that combines Tibotec’s darunavir (Prezista) with elvitegravir and GS 9350 is also a possibility if once-daily dosing of darunavir in protease inhibitor-experienced patients were to prove successful with GS 9350 boosting.