To the Editors:
Ritonavir is used to boost the pharmacokinetics (PKs) of protease inhibitors (PIs), typically at the dose of 100 mg once or twice daily. Ritonavir is available either as 100-mg tablets or in a liquid formulation, which is very poorly tolerated.1 There is no ritonavir tablet currently available at a dose lower than 100 mg. Maximal inhibition of CYP3A4 metabolism may take place at lower concentrations of ritonavir.2 Lower doses of ritonavir may also be better tolerated, cheaper to manufacture, and easier to coformulate with PIs.3 However, it is essential to establish whether lower doses of ritonavir have equal potential to boost PIs compared with the currently approved doses.
We have identified 4 cross-over PK trials of ritonavir at the doses of 50 mg versus 100 mg. These trials evaluated the PIs atazanavir (300/50 versus 300/100 mg once daily [OD]),4 darunavir (800/50 versus 800/100 mg OD),5 saquinavir (1500/50 versus 1500/100 mg OD),6 and amprenavir (600/50 versus 600/100 mg twice a day).7 These trials were conducted using the liquid formulation of ritonavir. Summary PK results are shown in Table 1.
Thirteen healthy volunteers (mainly white) were treated with atazanavir at doses of 300/50 and 300/100 mg once daily. The maximum concentration (Cmax) and 24-hour area under the curve (AUC) of atazanavir were bioequivalent for the 2 doses of ritonavir. The minimum concentration (Cmin) was slightly lower at the 50-mg dose, but this difference was not statistically significant.3 There were statistically significant rises in total cholesterol and low-density lipoprotein using the 300/100 mg OD dose but not with the 300/500 mg OD dose.4
Eighteen healthy volunteers (mainly white) were treated with darunavir/ritonavir at doses of 800/50 and 800/100 mg OD. The Cmax and 24-hour AUC of darunavir were both bioequivalent at the 2 doses.5 The geometric mean Cmin was 32% lower using the 50-mg dose of ritonavir, compared with the 100-mg ritonavir group, and this difference was statistically significant.5 A 20-mg boosting dose of ritonavir was evaluated, but the darunavir Cmax, AUC, and Cmin levels achieved with this dose were significantly lower than the reference 100-mg dose.5
A Thai cross-over PK study compared doses of 1500/50 mg with 1500/100 mg once daily, in 18 HIV-1–infected subjects. The mean Cmax, 24-hour AUC, and Cmin of saquinavir 1500 mg OD were 4%, 14%, and 24% higher, respectively, when used with the 50-mg dose, compared with the 100-mg dose of ritonavir,6 but none of these differences was statistically significant.
In a German cross-over PK study of 13 healthy volunteers,7 there was no difference in amprenavir AUC, Cmax, or Cmin using the 50 mg or 100 mg twice-daily doses of ritonavir. Bioequivalence comparisons were not reported in this study.
There was no difference in the variability of PI concentrations using the different doses of ritonavir, as shown by the standard deviations of mean darunavir and amprenavir concentrations or the interquartile ranges of saquinavir concentrations (Table 1).
These trials are too small and short term to evaluate potential differences in safety and tolerability between the 50 and 100 mg once-daily doses of ritonavir; larger studies would be required to investigate this issue. These results apply only to the 4 PIs studied; others such as lopinavir, indinavir, and tipranavir require doses of ritonavir of at least 100 mg twice daily for adequate boosting; lower doses are less effective at boosting for these PIs.2
Although the 50-mg dose and 100 mg dose of ritonavir led to bioequivalent AUC and Cmax levels of atazanavir and darunavir, there was a slightly lower Cmin level of these 2 PIs when boosted with the 50-mg dose of ritonavir. The clinical significance of this difference in Cmin is unknown, but would need to be investigated in larger studies, with efficacy endpoints. Small differences in Cmin between ritonavir boosting doses may have different consequences for treatment efficacy in PI-naive versus PI-experienced patients.
The cross-over trials included in this report were conducted using the liquid formulation of ritonavir. If a 50-mg heat-stable tablet of ritonavir can be manufactured, or coformulated with any of the 4 PIs evaluated, new bioequivalance PK trials would be required to ensure that the boosting effects were similar.
The costs of second-line treatment remain a barrier to access in developing countries.
A 50-mg ritonavir tablet could also be very useful for pediatric use, where doses of ritonavir below 100 mg are often required: liquid ritonavir is poorly tolerated in children and infants.
In summary, if lower doses of ritonavir are able to achieve bioequivalent drug levels of the PIs atazanavir, darunavir, saquinavir, and amprenavir, there is a strong justification for further research and development on a 50-mg strength tablet of ritonavir, and/or coformulations of lower dose ritonavir with these PIs.
1. . Abbott Laboarotories 2010 Ritonavir prescribing information Available at: http://www.rxabbott.com/pdf/norvirtab_pi.pdf
. Accessed October 11, 2011
2. Mathias AA, West S, Hui J, et al. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther. 2009;85:64–70 E-pub: September 24, 2008
3. Hill A, van der Lugt J, Sawyer W, et al. How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging trials. AIDS. 2009;23:2237–2245
4. Estevez E, Molto J, Tuneu L, et al. No changes in atazanavir exposure when boosted with 100 mg or 50 mg ritonavir in healthy volunteers. Presented at: International Workshop on HIV Pharmacology; April 2011; Miami, FL, Abstract P31
5. Tibotec Pharmaceuticals Ltd. . Phase I, open-label, randomized, 3-way crossover trial to assess the pharmacokinetics of darunavir (DRV) given once-daily with different doses of ritonavir in healthy subjects Available at: http://clinicaltrials.gov/ct2/show/NCT00744887?term=darunavir&rank=39
. Accessed October 11, 2011
6. van der Lugt J, Gorowara M, Avihingsanon A, et al. Reducing the boosting dose of ritonavir does not affect saquinavir plasma concentrations in HIV-1-infected individuals. AIDS. 2009;23:1176–1179
7. Kurowski M, Staszewski S, Arslan A, et al. Influence of 50 mg, 100 mg and 200 mg ritonavir (RTV) on the pharmacokinetics (PK) of amprenavir (APV) after multiple doses in healthy volunteers for once daily (OD) and twice daily (BID) regimens. Presented at: 1st IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, July 2001 [Abstract 351]