Conference Reports for NATAP

10th International Workshop on Clinical Pharmacology of HIV Therapy Amsterdam April 15-17, 2009 Back

How Much (or How Little) Ritonavir Do You Need to Boost Another PI?       10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam   Mark Mascolini   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 analyzed 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 "does 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 analyzed, dose dependence was not affected by the oral bioavailability of the PI or by each PI's effect 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 100-mg dose. Right now, when not coformulated with lopinavir, ritonavir comes as a 100-mg 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.   Reference 1. 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.