A dual protease inhibitor regimen of saquinavir and amprenavir boosted with low-dose ritonavir appears safe and effective as salvage therapy, as long as therapeutic drug level monitoring is carried out to individualise dosing of saquinavir. However, pill burden remains a concern with this twice daily experimental combination, according to the results of a small US study published in the August 1st issue of the Journal of Acquired Immune Deficiency Syndromes.
Researchers from the University of North Carolina enrolled nine highly treatment experienced men and two women – who had previously taken a median of 4.5 nucleosides (NRTIs), 1 non-nucleoside (NNRTI), and 3.5 protease inhibitors (PIs) – into a randomised, non blinded, prospective study. The study’s aims were to measure the change in saquinavir and amprenavir blood plasma levels when used together and boosted with low-dose ritonavir, and to evaluate 24-week safety and immunologic and virologic response.
In addition to the PIs nine of the participants also took tenofovir with a combination of either ddI (n = 3), 3TC (n = 3), d4T (n = 2), or abacavir (n = 1). One individual was prescribed abacavir/ddI, and one other received AZT/3TC.
During the first part of the study five participants were randomly assigned to receive saquinavir 1000mg/ritonavir 100mg every 12 hours, and the remaining six were given amprenavir 600mg/ritonavir 100mg every 12 hours. The participants who began the study on saquinavir soft-gel (Fortovase) capsules were changed to hard-gel saquinavir (Invirase) during the study, when data from Roche revealed similar drug levels and less potential side effects on Invirase. Everyone else received Invirase. Pharmacokinetic (PK) analysis revealed that drug levels of boosted saquinavir and boosted amprenavir alone were similar to previously published data.
After a median of nine days, the second full dose PI was added to everyone’s regimen, and PK analysis was repeated after a median of 16 days on double boosted PI therapy. When saquinavir was added to the boosted amprenavir regimen, there was a minimal change in amprenavir or ritonavir levels. However, the addition of amprenavir to the boosted saquinavir regimen resulted in significant decreases in both saquinavir and ritonavir levels. Three different protocols were followed to attempt to return all drugs to their single boosted levels. Increasing the saquinavir dose to 1400mg twice daily made no difference, and increasing the ritonavir dose to 200mg every 12 hours increased saquinavir and ritonavir levels only somewhat.
However, for the seven participants who increased their saquinavir dose to 1400mg and ritonavir dose to 200mg, both every 12 hours, alongside 600mg of amprenavir, mean total exposure (AUC) and minimum levels (Cmin) of saquinavir were 62% and 88% of single boosted saquinavir levels, respectively; the mean total exposure and minimum levels of amprenavir were 149% and 171% of single boosted amprenavir levels, respectively; and the mean AUC and Cmin of ritonavir were almost twice as high with this dosing strategy than when used as a single booster agent. The authors note, “The high pill burden precluded any further increase in dosing; however, with this regimen, saquinavir and ritonavir exposures were similar to the saquinavir 1000mg/ritonavir 100mg twice-daily regimen.”
Although nine of eleven participants were also taking tenofovir, which has been shown to interact with NRTI and PI levels, “it did not appear that tenofovir affected the pharmacokinetics of our PI regimen, although our numbers were too small for formal comparisons.”
All remaining participants were then given this dose of the PIs, and after eight weeks viral load decreased by 1.32 (range 0.28–2.63) log10 (ten participants included). At 16 weeks viral load had decreased 0.98 (0.13–2.69) log10 (nine participants included). At 24 weeks viral load was reduced by a mean of 1.55 (0.21–2.88) log10 in the six individuals still on therapy. CD4 counts increased a mean of 46 (-92 to 172) cells/mm3 at 16 weeks and 52 (-22 to 185) cells/mm3 at 24 weeks.
Four participants left the study due to poor adherence (98% adherence. However, everyone experienced mild diarrhoea, which improved after about two weeks, although six participants had loose stools throughout the study, which they controlled with anti-diarrhoea medication. Another participant left the study at 16 weeks due to grade two hepatotoxicity. Fasting blood glucose levels did not change over 24 weeks, although triglycerides increased by a mean of 314 (40–1071) mg/dl, and cholesterol increased by a mean of 43 (12–110) mg/dl over 24 weeks. Although the triglycerides and cholesterol levels increased as expected with ritonavir treatment, the authors say that “they did not appear directly related to increasing ritonavir dosing from 100mg to 200mg twice daily,” since three of the four individuals with triglyceride elevations at 24 weeks had elevated triglycerides at baseline.
Despite the high pill burden, the authors suggest that double boosting saquinavir and amprenavir is a good choice compared with other double boosting strategies that use, for example, Kaletra and another PI, because “HIV-1 isolates with resistance to amprenavir have demonstrated hypersusceptibility to saquinavir. Additionally, amprenavir and saquinavir are synergistic when combined in vitro.”
A new formulation of amprenavir, fosamprenavir, is now available that could reduce the pill burden from four capsules to one pill every twelve hours. A 500mg tablet of saquinavir is currently being developed by Roche that should reduce pill burden even more. However, more PK studies are needed.
Further information on this website
Double-boosted saquinavir/atazanavir study lays ground for PI-only regimen - news story
Choosing a salvage regimen - overview
Corbett AJ et al. The pharmacokinetics, safety, and initial virologic response of a triple–protease inhibitor salvage regimen containing amprenavir, saquinavir, and ritonavir. J Acquir Immune Defic Syndr 36: 921–928, 2004