Ritonavir dose of 50 mg could be sufficient to boost some protease inhibitors, trials needed

A 50 mg dose of ritonavir (Norvir) could be sufficient as boosting agent for certain protease inhibitors, UK investigators suggest in the December 15^th edition of the Journal of Acquired Immune Deficiency Syndromes.

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 discontinued).   

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 ritonavir dose.

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.

 “These trials 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 this issues.”

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.”