A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus
K. Gallicano et al., A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus, CLIN PHARM, 70(2), 2001, pp. 149-158
Aim: Our primary aim was to evaluate the plasma exposures and safety of rif
abutin and its active 25-O-desacetyl metabolite during concomitant therapy
of intermittent rifabutin dosing regimens with a combination of ritonavir a
nd saquinavir.
Methods: Twenty-four patients without mycobacterial infection who were huma
n immunodeficiency virus seropositive and who were receiving 400 mg each of
ritonavir and saquinavir twice daily participated in a 3-period, 2-group l
ongitudinal pharmacokinetic study. Patients were equally randomized to rece
ive 300 mg of rifabutin every 7 days (group 1) or 150 mg of rifabutin every
3 days (group 2) for 8 weeks. Blood samples were collected over the dosing
intervals of the protease inhibitors at baseline (period 1) and of the 3 d
rugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement o
f plasma concentrations of the 3 drugs and 25-O-desacetylrifabutin.
Results: Nineteen patients (group 1, n = 10; group 2, n = 9) completed the
study. Five individuals withdrew from the study; 3 of them experienced side
effects, and 2 were lost to follow-up. For combined groups, mean saquinavi
r and ritonavir overall (area under the concentration-time curve [AUC]) and
peak (C,,a.,) plasma exposures averaged over periods 2 and 3 did not chang
e significantly (8% to 19%; P > .05) compared with those in period 1 (90% c
onfidence intervals, -7% to 26% for ritonavir and -2% to 38% for saquinavir
). Rifabutin and metabolite AUC and C-max exposures were stable over the 8
weeks, with intraindividual coefficients of variation of 12% to 19%. Oral c
learance of rifabutin was similar in both groups (321 mL/min in group 2 ver
sus 372 mL/min in group 1; P = .34). Rifabutin C-max values were significan
tly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rif
abutin and metabolite predose levels were significantly higher in group 2 (
rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 2
8 ng/mL; P < .002).
Conclusions: Rifabutin exposures were similar at 4 and 8 weeks and had mini
mal effect on ritonavir and saquinavir exposures. Intermittent rifabutin do
sing over 8 weeks provided a safe and manageable regimen for concurrent the
rapy with a combination of ritonavir and saquinavir.