Systematic review of 17 dose-ranging pharmacokinetic trial

How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials.

Ritonavir has been evaluated at boosting doses of 50-800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor. For the five pharmacokinetic trials of lopinavir/ritonavir, a meta-analysis was used to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics. Saquinavir, fosamprenavir and darunavir were boosted equally well by lower (50-100 mg) versus higher doses of ritonavir. Indinavir, tipranavir and lopinavir were boosted more by higher ritonavir doses. Data on atazanavir were inconclusive. The ritonavir dose-dependence of boosting effects did not correlate with their bioavailability or their effects on ritonavir plasma levels. Atazanavir and indinavir raised plasma ritonavir levels by 69-72%, whereas saquinavir had no effects on ritonavir. Darunavir, lopinavir, tipranavir and fosamprenavir all lowered ritonavir plasma levels. For the meta-analysis of lopinavir/ritonavir trials, the 200/150 mg twice daily (b.i.d.) dose of lopinavir/ritonavir (one Meltrex 200/50 mg tablet and one ritonavir 100 mg b.i.d.) showed lopinavir area under the curve and minimum concentration similar to the standard 400/100 mg b.i.d. dose. It may be possible to use three protease inhibitors (saquinavir, amprenavir and darunavir) with lower doses of ritonavir. A 200/150 mg b.i.d. dose of lopinavir/ritonavir could lower costs while maintaining very similar lopinavir plasma levels to the standard dose. New pharmacoenhancer drugs may need to be used at different doses to boost different antiretrovirals.

A boosted protease inhibitor plus two nucleoside analogues (NRTIs) are recommended by WHO for second line antiretroviral treatment, with atazanavir and lopinavir being the preferred options. For boosted protease inhibitors, an optimal safety profile depends on both the choice of protease inhibitor and the lowest dose of ritonavir possible. The dose-ranging pharmacokinetic trials that are reported in the public domain here suggest that the pharmacokinetics of lopinavir are highly dependent on the dose of ritonavir used, as well as the lopinavir dose. This suggests that a crossover dose-ranging trial of lopinavir/ritonavir would help determine whether 400/100 mg versus 200/150 mg doses, for example, provide the optimum pharmacokinetics with lowest toxicity.