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A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus
Author(s) -
Gallicano Keith,
Khaliq Yasmin,
Carignan Germain,
Tseng Alice,
Walmsley Sharon,
Cameron D. William
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2001.117612
Subject(s) - ritonavir , rifabutin , saquinavir , pharmacokinetics , medicine , cmax , dosing , pharmacology , gastroenterology , viral load , immunology , clarithromycin , human immunodeficiency virus (hiv) , antiretroviral therapy , helicobacter pylori
Aim Our primary aim was to evaluate the plasma exposures and safety of rifabutin and its active 25‐O‐desacetyl metabolite during concomitant therapy of intermittent rifabutin dosing regimens with a combination of ritonavir and saquinavir. Methods Twenty‐four patients without mycobacterial infection who were human immunodeficiency virus seropositive and who were receiving 400 mg each of ritonavir and saquinavir twice daily participated in a 3‐period, 2‐group longitudinal pharmacokinetic study. Patients were equally randomized to receive 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 drugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement of 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 saquinavir and ritonavir overall (area under the concentration‐time curve [AUC]) and peak (C max ) plasma exposures averaged over periods 2 and 3 did not change significantly (8% to 19%; P > .05) compared with those in period 1 (90% confidence 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 clearance of rifabutin was similar in both groups (321 mL/min in group 2 versus 372 mL/min in group 1; P = .34). Rifabutin C max values were significantly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rifabutin and metabolite predose levels were significantly higher in group 2 (rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 28 ng/mL; P < .002). Conclusions Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing over 8 weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir. Clinical Pharmacology & Therapeutics (2001) 70 , 149–158; doi: 10.1067/mcp.2001.117612