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


METHODS
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.


RESULTS
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 200/50mg tablet and one ritonavir 100mg b.i.d.)showed lopinavir area under the curve and minimum concentration similar to the standard 400/100mg b.i.d. dose.


CONCLUSIONS
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 pharmaco enhancer drugs may need to be used at different doses to boost different antiretrovirals.
Hill
Andrew
A
van der Lugt
Jasper
J
Sawyer
Will
W
Boffito
Marta
M
D002986:Clinical Trials as Topic; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D061466:Lopinavir; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir