Two novel ‘enhancer’ drugs boost protease inhibitors as much as ritonavir

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Two novel pharmacokinetic-enhancing agents - GS 9350 and SPI-425 - appear to work as well as ritonavir (Norvir) for boosting protease-inhibitor levels, but with fewer side-effects, according to presentations on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.

Ritonavir interferes with a liver enzyme called cytochrome P450 3A (CYP3A) that metabolises many medications. By slowing their processing, ritonavir can help maintain effective levels of protease inhibitors in the blood, and current treatment guidelines recommend that these drugs should usually be boosted with a small dose of ritonavir.

But ritonavir has some drawbacks, including its tendency to cause metabolic side-effects such as elevated cholesterol, and the fact that a single company controls how it can be used.


Investigators from Gilead Sciences looked for a drug that would have boosting ability similar to ritonavir, but without anti-HIV activity.


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.


A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.


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.


A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).

They first examined GS 9350 in test-tube studies using human liver cells, finding that it is a potent inhibitor of CYP3A. They also found that the drug had no activity against HIV itself, and had less impact than ritonavir on lipids and glucose in fat cells.

In a proof-of-concept trial, 36 healthy HIV-negative volunteers received either increasing doses of GS 9350 (50mg, 100mg and 200mg once daily) or 100mg of ritonavir or a placebo for two weeks (with 18 people in each arm of the study). They also took midazolam, a sedative drug metabolised by CYP3A that can be used as a 'probe' to test for changes in CYP34 activity.

Both the 100mg and 200mg GS 9350 doses showed similar boosting ability to 100mg of ritonavir, reducing clearance of midazolam by 92%, 95% and 95%, respectively. GS 9350 was generally well tolerated, with no severe clinical or laboratory adverse events and no apparent effect on electrical conduction of the heart.

Finally, investigators created fixed-dose 'quad' pills that combined 100mg or 150mg of GS 9350, plus Gilead's experimental HIV integrase inhibitor elvitegravir, plus 300mg of tenofovir and 200mg of emtricitabine (the two drugs in the Truvada pill).

In a study of 44 HIV-negative volunteers, the four-in-one pill containing either the 100mg or the 150mg dose of GS 9350 boosted elvitegravir in the blood to an effective level. Again, treatment was generally well tolerated.

Gilead has said in a press statement that it will continue with further trials of GS 9350, including both a head-to-head study comparing the four-in-one co-formulated pill versus the three-in-one Atripla pill (efavirenz/tenofovir/emtricitabine) in treatment-naive HIV patients (scheduled to start within a few months), and an ongoing study of GS 9350 as a stand-alone booster of atazanavir (Reyataz).


Investigators from Sequoia Pharmaceuticals also presented data from a set of studies looking at an experimental enhancer, SPI-452.

Test-tube studies using human liver cells showed that SPI-452 was a potent inhibitor of CYP3A, and that it slowed metabolism of approved HIV protease inhibitors, as well as the experimental hepatitis-C-virus protease inhibitor boceprevir. Like the Gilead drug, SPI-425 also had no activity against HIV.

In rats and dogs, SPI-452 boosted blood levels of the protease inhibitors saquinavir (Invirase), lopinavir (marketed as Kaletra when co-formulated with ritonavir) and atazanavir.

In the first human clinical trial of the drug, 58 HIV-negative volunteers received single escalating doses of SPI-425 (25, 50, 100, 200, 400 and 600mg). In the second part of the study, participants received either 50mg or 200mg of SPI-425 plus 1000mg of saquinavir, or else saquinavir or placebo alone.

SPI-425 was found to increase saquinavir levels markedly in a dose-proportional manner. SPI-425 was generally well tolerated, with mild headache or sore throat being the most commonly reported adverse events.

The last reported study was a proof-of-concept trial involving 67 healthy HIV-negative individuals randomly assigned to take 25mg, 50mg or 200mg of SPI-425 or placebo once daily for 15 days. On day 15, they added darunavir (Prezista), atazanavir or placebo; on day 16, they took the second drug again without SPI-452.

Over 24 hours, SPI-425 significantly increased minimum plasma darunavir levels by as much as 37-fold, and atazanavir levels by up to 13-fold. Here too, SPI-425 was well tolerated, with the most common adverse events being mild headache, nausea or vomiting, and diarrhoea. There were no significant changes in triglyceride or LDL ('bad') cholesterol, liver-function tests or electrical conduction of the heart.

Sequoia has filed investigational new drug applications with the US Food and Drug Administration for SPI-425 and for an experimental HIV protease inhibitor (SPI-256), suggesting it may have plans for a co-formulation that could be an alternative to Kaletra.

Speaking at a press conference in Montreal, presenter Robert Guttendorf said Sequoia was also exploring SPI-452 and other enhancer candidates to aid treatment of hepatitis C, and possibly even non-viral diseases.


Mathias A et al. GS-9350: A pharmaco-enhancer without anti-HIV activity. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 40, 2009.

Gulnik S et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 41, 2009.