About The Study
Part I of the study entered 24 participants who were currently receiving a combination of saquinavir and ritonavir and determined if rifabutin, when given with both ritonavir and saquinavir, could be given once or two times a week instead of once daily It also observed the safety and tolerance of the three drugs during eight weeks of coadministration. Part II of the study will enter 12 participants on a combination of ritonavir (200 mg bid) and indinavir (600 mg bid), evaluate the effect of rifabutin on indinavir and ritonavir, and determine if 150 mg rifabutin administered twice a week in the presence of ritonavir and indinavir will give comparable exposure to rifabutin as 300 mg rifabutin administered alone once daily. It will also observe the safety and tolerance of the three drugs during five weeks of coadministration.
Study Approach
Study part I was a two-centre, randomized, three-period, two-group pharmacokinetic (drug activity) study. In period 1, all participants continued their antiretroviral therapy alone and the blood concentrations of the two protease inhibitors were determined on day 1. In period 2 and 3, participants were assigned to receive either 300 mg every seven days (group 1) or 150 mg every three days (group 2) of rifabutin in the morning for eight weeks with the protease inhibitors. In period 2, blood pharmacokinetics of rifabutin, ritonavir and saquinavir were assessed over their dosing intervals after four weeks of concomitant administration. In period 3, the same pharmacokinetic evalutations were performed after eight weeks of concomitant administration.
Study population
Men and women who were infected with HIV (CD4 count above 75 cells/mm3), between the ages of 18 and 60 years, and who were receiving combination ritonavir and saquinavir, each at a dose of 400 mg twice daily for at least two weeks, were eligible to participate in part I of the study. Ottawa General and Toronto Hospital enrolled 24 participants, 19 of whom completed the study, including 18 men and 3 women. The mean age was 39.7, the median CD4 count at study entry was 480 cell/mm3.
Results
Results of part I of the study are available. Nineteen participants completed that part of the study. Three participants experienced side effects, and two were lost to follow-up. For group 1 and 2 combined, mean saquinavir and ritonavir overall and peak blood concentrations averaged over periods 2 and 3 did not change significantly compared to those in period 1. Rifabutin blood concentrations were stable over the 8 weeks, with intraindividual coefficients of variation of 12% to 19%. Oral clearance of rifabutin was similar in both groups. Ribafutin peak values were significantly lower in group 2 (310 ng/ml versus 496 ng/ml in group 1). Rifabutin predose levels were also significantly higher in group 2 (54 ng/ml versus 17 ng/ml).
Conclusions
Rifabutin exposures were similar at four and eight weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing (150 mg every three days or 300 mg every seven days) over eight weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir.
Note: These results were taken from an article published in Clinical Pharmacology & Therapeutics, Volume 70, Number 2: 149-158.