A 50 mg dose of ritonavir (Norvir) could be sufficient as boosting agent for
certain protease inhibitors, UK investigators suggest in the December 15th
edition of the Journal of Acquired Immune
Researchers from Liverpool University and London’s Chelsea
and Westminster Hospital analysed the results of a number of small
pharmacokinetic studies to see if a ritonavir boosting dose of 50 mg was
equivalent to the 100 mg used in routine practice.
“There was no difference in the variability of PI [protease
inhibitor] concentrations using the different doses of ritonavir,” comment the
researchers. “Lower doses of ritonavir…may be better tolerated, cheaper to
manufacture, and easier to coformulate with other PIs.”
All the recommended protease inhibitors used in routine HIV
care have their potency boosted by ritonavir. The standard dose of this drug is
100 mg once or twice daily.
The drug works by blocking the CYP3A4 metabolism, therefore
increasing blood levels of the accompanying full-dose protease inhibitor
However, it is possible that the CYP3A4 pathway may be
blocked with a smaller dose of ritonavir.
Investigators identified four small pharmacokinetic studies
where 50 mg and 100 mg doses of ritonavir were used as boosting agents for
atazanavir (Reyataz), darunavir (Prezista), saquinavir (Invirase) and amprenavir (now
There is no ritonavir 50 mg tablet and individuals in these
studies were therefore treated with the liquid formulation of the drug, which
can be poorly tolerated.
The atazanavir study involved 13 HIV-negative volunteers.
They were treated with a daily dose of atazanavir/ritonavir of 300/100 mg or
300/50 mg. Maximum and 24-hour area under the curve concentrations of
atazanavir were equivalent. However, slightly lower minimum concentrations of atazanavir were observed with the 50 mg
Eighteen HIV-negative individuals were recruited to the
darunavir/ritonavir study. They received darunavir/ritonavir doses of 800/100
mg or 800/50 mg once daily. Both maximum and steady-state concentrations of
darunavir were equivalent for the 100 mg and 50 mg boosting doses. However,
minimum levels of the drug were a significant 32% lower when the 50 mg dose of
ritonavir was used.
A total of 18 HIV-positive individuals participated in the
saquinavir study. They received a 1500 mg daily dose of saquinavir boosted by
100 mg or 50 mg of ritonavir. Levels of saquinavir were slightly higher with
the 50 mg ritonavir dose.
Finally, the amprenavir study recruited 13 HIV-negative
individuals. The 100 mg and 50 mg boosting doses showed bioequivalence.
are too small and short term to evaluate potential differences in safety and
tolerability between the 50 mg and 100 mg once-daily doses of ritonavir,”
caution the investigators. “Larger studies would be required to investigate
Nevertheless, they believe that a 50 mg dose of the drug
could have several advantages, especially for pediatric use “where doses of
ritonavir below 100 mg are often required: liquid ritonavir is poorly tolerated
in infants and children.”
They conclude, “if lower doses of ritonavir are able to
achieve bioequivalent drug levels of the PIs atazanavir, darunavir, saqunavir,
and amprenavir, there is a strong justification for further research and
development of a 50 mg strength tablet of ritonavir, and/or coformulations of
lower dose ritonavir with these PIs.”