Much Ritonavir (Norvir) Is Needed to Boost HIV Protease
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.
(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.
has been evaluated at boosting doses of 50 to 800 mg
daily in combination with 7 PIs: amprenavir
(Invirase), and tipranavir
(Aptivus). In 2007, amprenavir was discontinued
in favor of its more bioavailable pro-drug fosamprenavir
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.
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.
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
fosamprenavir, and darunavir were boosted as well
by a lower 50 to 100 mg ritonavir dose as they were
by a higher dose.
tipranavir, and lopinavir, in contrast, were boosted
more when using higher ritonavir doses.
on atazanavir were inconclusive.
dose-dependence of ritonavir's boosting effects
did not correlate with bioavailability or effects
on ritonavir plasma levels.
and indinavir raised ritonavir plasma ritonavir
levels by 69% to 72%, whereas saquinavir had no
effect on ritonavir concentrations.
lopinavir, tipranavir, and fosamprenavir all lowered
ritonavir plasma levels.
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.
adverse event profile of boosted PIs was affected
by both ritonavir dose and the specific side effects
associated with the various PIs.
may be possible to use 3 protease inhibitors (saquinavir,
amprenavir, and darunavir) with lower doses of ritonavir,"
the study authors concluded. "A 200/150 mg [twice-daily]
dose of lopinavir/ritonavir could lower costs while maintaining
very similar lopinavir plasma levels to the standard dose."
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."
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
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."
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."
companies are now working on at least 2
novel pharmacoenhancers that might be used instead
of ritonavir for antiretroviral boosting.
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,