How Much Ritonavir (Norvir) Is Needed to Boost HIV Protease Inhibitors?

		SUMMARY: It may be possible to use certain HIV protease inhibitors (PIs) with lower boosting doses of ritonavir, according to an article published in the November 13, 2009 issue of the journal AIDS. A systemic review of prior trials showed that a 50-100 mg dose of ritonavir boosted 3 PIs -- saquinavir, fosamprenavir, and darunavir -- as much as higher doses. In the case of lopinavir/ritonavir, however, raising the ritonavir dose by a small amount enabled reduction of the lopinavir dose, potentially lowering costs.

The PI ritonavir (Norvir) strongly inhibits the activity of certain CYP450 enzymes in the liver, which has the effect of slowing metabolism of many other drugs -- including other PIs -- thereby raising their concentration in the blood and allowing for lower or less frequent dosing.

Ritonavir has been evaluated at boosting doses of 50 to 800 mg daily in combination with 7 PIs: amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezista) indinavir (Crixivan), lopinavir (Kaletra), saquinavir (Invirase), and tipranavir (Aptivus). In 2007, amprenavir was discontinued in favor of its more bioavailable pro-drug fosamprenavir (Lexiva).

Even at standard low boosting doses -- typically 100 or 200 mg -- ritonavir can cause side effects including gastrointestinal symptoms and blood lipid abnormalities. Minimizing the boosting dose could potentially improve tolerability and lower the cost of therapy.

Andrew Hill and colleagues performed a systematic review of prior studies of ritonavir boosting. They conducted a search of the MEDLINE medical literature database that identified 17 pharmacokinetic trials using different ritonavir doses with various PIs.

Ritonavir doses were correlated with plasma levels of each boosted PI. For the 5 pharmacokinetic trials of lopinavir/ritonavir -- which is marketed as a fixed-dose combination pill -- they performed a meta-analysis to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics.

Results

	Saquinavir, fosamprenavir, and darunavir were boosted as well by a lower 50 to 100 mg ritonavir dose as they were by a higher dose.
	Indinavir, tipranavir, and lopinavir, in contrast, were boosted more when using higher ritonavir doses.
	Data on atazanavir were inconclusive.
	The dose-dependence of ritonavir's boosting effects did not correlate with bioavailability or effects on ritonavir plasma levels.
	Atazanavir and indinavir raised ritonavir plasma ritonavir levels by 69% to 72%, whereas saquinavir had no effect on ritonavir concentrations.
	Darunavir, lopinavir, tipranavir, and fosamprenavir all lowered ritonavir plasma levels.
	In the lopinavir/ritonavir meta-analysis, a 200/150 mg twice-daily dose (1 Kaletra Meltrex 200/50 mg tablet plus 1 ritonavir 100 mg tablet) produced a minimum drug concentration and area under the curve (a measure of total concentration between doses) similar to those seen with the standard 400/100 mg twice-daily dose.
	The adverse event profile of boosted PIs was affected by both ritonavir dose and the specific side effects associated with the various PIs.

The currently available minimum ritonavir tablet strength is 100 mg, but 2 trials have evaluated 50 mg doses using the liquid formulation. "These suggest that 50 mg doses are sufficient to boost either saquinavir or fosamprenavir," the researchers wrote. "It is unknown whether a 50 mg dose of ritonavir could also boost darunavir or atazanavir to the same extent as the approved 100 mg dose."

A 50 mg dose of ritonavir might be easier to co-formulate with PIs, the researchers suggested, which could improve adherence (by reducing the required number of pills) as well as lowering costs. They also noted that a 50 mg ritonavir tablet would be very useful for pediatric use.

"Further clinical trials evaluating saquinavir, atazanavir, fosamprenavir and darunavir with lower doses of ritonavir are warranted to define the minimum dose of ritonavir required for boosting," they recommended. "Results from these trials could help to justify development of new heat-stable ritonavir tablets at lower doses."

"This systematic review shows that ritonavir has dose-dependent boosting effects on the protease inhibitors lopinavir, indinavir, [and] tipranavir, but lower and higher doses of ritonavir appear to have equal effects on saquinavir, fosamprenavir, and darunavir," the authors wrote. "These results may help in the design of dose-ranging trials of other pharmacoenhancers currently in development."

Pharmaceutical companies are now working on at least 2 novel pharmacoenhancers that might be used instead of ritonavir for antiretroviral boosting.

11/06/09

Reference
A Hill, J van der Lugt, W Sawyer, and M Boffito. How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials (Editorial Review). AIDS 23(17): 2237-2245, November 13, 2009. (Abstract).