Important note: Information in this article was accurate in May 2009. The state of the art may have changed since the publication date.
How much (or how little) ritonavir do you need to boost another PI?
HIV Treat Bull - 2009 May-Jun;10(5/6): 25
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:
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.
2009-05-10
IB2009-05-25
©2009. I-BASE HIV Treatment Bulletin. Permission to reproduce courtesy of HIV i-Base, Third Floor East, Thrale House, 44-46 Southwark Street, London SE1 1UN - T: +44 (0) 20 7407 8488 F: +44 (0) 20 7407 8489
AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted grants from the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2009. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1980, 2009. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.