How much (or how little) ritonavir do you need to boost another PI?

Mark Mascolini, natap.org

Protease inhibitors (PIs) fall into two groups – those whose concentration correlates closely with the boosting dose of ritonavir, and those that do not – according to a 16-study systematic analysis by Andrew Hill (University of Liverpool) and colleagues at other centers. [1]

Finding the lowest effective boosting dose could cut costs and lower the risk of side effects. Hill suggested 50 mg of ritonavir once daily – or less – may be enough to boost some PIs.

Hill analysed results of 16 PI/ritonavir dose-ranging studies:

Four amprenavir or fosamprenavir trials with ritonavir doses ranging from 50 mg twice daily to 200 mg twice daily
One atazanavir cohort study with ritonavir doses ranging from 100 to 200 mg once daily
One darunavir trial with ritonavir doses ranging from 100 mg once daily to 200 mg twice daily
One indinavir trial with ritonavir doses ranging from 100 to 400 mg twice daily
Three saquinavir trials with ritonavir doses ranging from 50 mg once daily to 400 mg twice daily
One tipranavir trial with ritonavir doses ranging from 100 to 200 mg twice daily
Five lopinavir trials with ritonavir doses ranging from 50 mg twice daily to 266 mg twice daily

For each PI, Hill calculated the geometric mean ratio for the boosted PI with higher versus lower doses of ritonavir. For the five lopinavir/ritonavir trials, he performed a meta-analysis of geometric mean ratio data to estimate the effect of the lopinavir dose versus the ritonavir dose on area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin).

The overall analysis showed that boosted PIs fell into two groups: PIs whose concentration depended on the size of the ritonavir boost (the dose-dependent group), and PIs whose concentration did not depend on the size of the ritonavir boost (the dose-independent group). Hill clarified that dose independence does not mean levels of that PI would be the same with or without ritonavir. Indinavir, lopinavir, and tipranavir are dose-dependent PIs, while (fos)amprenavir, darunavir, and saquinavir are dose-independent PIs.

Limited data from a cohort study suggest that atazanavir is a dose-independent PI, but Hill could not confidently classify it based on results presented to date. For all the PIs analysed, dose dependence was not affected by the oral bioavailability of the PI or by the effect of each PI on ritonavir concentrations.

These studies showed that 50 mg of ritonavir is enough to boost saquinavir once daily or fosamprenavir twice daily. Hill cautioned that the saquinavir finding comes from a single study. Similarly, the darunavir, tipranavir, and indinavir findings rest on one study each. The minimum ritonavir boosting dose for darunavir and atazanavir remains to be defined, Hill proposed, but it may also be under 100 mg.

The lopinavir/ritonavir meta-analysis showed that lopinavir AUC, Cmax, and Cmin rose proportionally as the ritonavir dose increased. But lopinavir AUC, Cmax, and Cmin did not rise in a proportional manner as the lopinavir dose rose. Hill figured that a 200/150-mg twice-daily dose of lopinavir/ritonavir (one Meltrex 200/50-mg tablet plus one 100-mg dose of ritonavir twice daily) would yield a lopinavir AUC, Cmax, and Cmin within 10% to 20% of those values with the 400/100-mg twice-daily dose (two Meltrex 200/50-mg tablets twice daily). He suggested these findings may mean that a higher ritonavir dose could be used with a lower dose of other dose-dependent PIs to achieve the same drug levels.

Hill concluded that a lower-dose ritonavir tablet -50 mg or less – could lower costs and improve tolerability, while boosting several commonly used PIs to a similar level compared with the current 100mg dose. Right now, when not coformulated with lopinavir, ritonavir comes as a 100mg soft-gel capsule. He also suggested these findings may be helpful in designing new PI boosters, because the ritonavir results show that different doses of a booster may be required to boost different PIs or other boostable drugs.

Comment

Whether lower ritonavir-boosting doses might be equally effective has been a long-standing question raised by community advocates since the first days of PI-boosting. Studies have been limited by the only formulation being the 100mg capsule. However, the availability of the new non-refrigerated meltrex tablet formulation of ritonavir, hopefully in 100mg and 50mg tablets will broaden these options.

While this study is interesting from a theoretical perspective, the interpatient variability of drug levels associated with protease inhibitors means that clinical studies and individual therapeutic level monitoring (TDM) will be essential before considering modification of the currently recommended doses.

Reference:

Hill A, van der Lugt J, M. Boffito M. How much ritonavir is needed to boost protease inhibitors? Systematic review of 16 dose-ranging PK trials. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract O_07.