Gilead now testing ritonavir replacement in human studies

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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.


boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.


The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

phase I

The first stage of human testing of a new drug or intervention, typically involving a small number (10-100) of participants who do not have the condition the drug is intended to treat. Phase I clinical trials evaluate safety, side-effects, dosage and how a drug is metabolised and excreted in the body.

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.

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.