A 32-day study of the pharmacokinetics (PK) of the protease inhibitors (PIs) hard-gel saquinavir (Invirase) and atazanavir (Reyataz), boosted by 100mg of ritonavir (Norvir) has found that the plasma concentrations of saquinavir and ritonavir were significantly enhanced, and that atazanavir further enhanced the boosting effect of ritonavir on saquinavir.
One of the researchers involved in the study has told aidsmap.com that although a further trial of clinical effectiveness will be needed, the findings may lay the foundation of a protease-only regimen for patients who have resistance to non-nucleosides (NNRTIs) and are unable to tolerate any nucleoside analogues that might still be active (NRTIs).
The study, which was conducted by London’s Chelsea and Westminster Hospital and supported by Invirase’s manufacturers Roche, was conducted in 18 patients who were already receiving saquinavir/ritonavir, supported by various NRTIs.
At the start of the study, all who were taking soft-gel saquinavir (Fortovase) at the usual doses of 800 or 1000mg twice a day, and patients taking the hard-gel capsules at 800mg or 1000mg a day were all switched to a standardised dose of 1600mg of hard-gel saquinavir (eight capsules) once a day, and baseline saquinavir PK measurements were performed. This was to standardise the dose given and enable researchers to plot out a 24-hour PK curve for all three PIs.
A day after this and for 31 days thereafter atazanavir at the standard dose of 300mg once a day was added. Patients then returned to their normal regimen.
Pharmacokinetic measurements on PI plasma levels were taken eleven days before the trial, on day 1 and then on day 2 at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after dosing.
All patients were also taking 100mg of ritonavir twice daily and various NRTIs – these included 3TC (eleven patients), abacavir (seven), tenofovir (six), ddI (five), AZT (five) d4T and ddC (one patient each).
Addition of atazanavir boosted the trough levels of saquinavir 112% over baseline, peak levels by 42%, area under the curve (AUC - total drug dose available) by 60% and extended the saquinavir half-life by 17%.
Atazanavir reduced the trough levels of ritonavir by 28% and the half-life by 17% (this latter result was not statistically significant); but peak levels were boosted by 58% and AUC by 41%.
Atazanavir PK levels were observed to be similar to those observed in a standard atazanavir/ritonavir regimen.
Significantly, although tenofovir has been shown to reduce both boosted and unboosted atazanavir levels, in this study the patients on tenofovir had levels of atazanavir that were 29% higher than patients not taking tenofovir.
No patient was taking an NNRTI or any medication known to have pharmacokinetic interactions with PIs. Nine patients had viral loads under 50 copies/ml and two had viral loads marginally above this figure (57 and 61). Median CD4 count was 442 cells/mm3 (range 118-947). Two of the study participants were women. All patients had normal haemoglobin and bilirubin counts and liver function.
A third of patients developed significant (grade 3-4) elevated bilirubin levels (hyperbilirubinemia). Scleral icterus (yellowing of the whites of the eyes) was observed in 22% and 11% developed jaundice – the latter has been observed in 5-15% of patients in other atazanavir studies.
However, though these results are comparable to those observed in other atazanavir studies, the study was not powered to show whether these side effects were raised above levels normally seen. The investigators comment that further trials could be conducted using lower doses of atazanavir to see if hyperbilirubinemia could be reduced.
Liver function tests remained normal in all patients. During the three-PI regimen period two patients each (11%) had diarrhoea and fatigue and one had headache.
Triglyceride, total cholesterol and glucose levels remained unchanged throughout the study and at a follow-up visit.
The investigators point out that the atazanavir cannot be giving the additional boost to saquinavir observed in this study, because ritonavir would be expected to compete more effectively to inhibit the CYP 3A4 enzyme (the mechanism by which saquinavir levels are boosted). They speculate that atazanavir boosts saquinavir by a different mechanism, possibly by inhibiting P-glycoprotein, a molecule that ‘shunts’ drugs out of cells.
Dr Mark Nelson, one of the study investigators, discussed the significance of the study.
“The BMS 045 study [Badaro et al] compared boosted atazanavir and boosted lopinavir (Kaletra®) and found them similarly potent. However there was a third arm combining unboosted atazanavir with saquinavir.
“This was done because it was known atazanavir boosted saquinavir levels and it was hoped combining the two drugs might avoid any residual lipid-raising effects of the ritonavir.
“However the saquinavir/atazanavir combination significantly underperformed [by a factor of 30-45%].
“This study now raises the possibility of a once-daily protease-only regimen for patients who have failed on NNRTIs and cannot tolerate available nucleosides.
“Atazanavir and saquinavir do not share signature primary resistance mutations, and there is incomplete evidence that a large accumulation of mutations would be necessary to covey resistance to both drugs. In any case, in the 045 study, patients on saquinavir/atazanavir with fewer than four PI mutations did just as well as patients on the other regimens.
“Although we need to do a proper clinical effectiveness trial in the absence of NRTIs, this study raises hope that a relatively non-toxic and resistance-proof regimen consisting solely of PIs may be available to patients who need it.
“The high pill count (eleven PI capsules once a day) will be reduced to six when a new 500mg formulation of saquinavir becomes available soon.”
References
Boffito M et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen. AIDS 2004, 18:1291-1297.
Badaro R et al. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI on patients who have experienced virologic failure to multiple HAART regimens: 16-week results from BMS A1424-045. 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, 2003. Abstract 118.