Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.
BACKGROUND
Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens.


METHODS
Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period.


RESULTS
Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours.


CONCLUSIONS
Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.
Hamzeh
Fayez M
FM
Johns Hopkins Hospital, Johns Hopkins University, Osler 527, 600 N. Wolfe Street, Baltimore, MD 21287-5554, USA.
Benson
Constance
C
Gerber
John
J
Currier
Judith
J
McCrea
Jackie
J
Deutsch
Paul
P
Ruan
Ping
P
Wu
Hulin
H
Lee
Jin
J
Flexner
Charles
C
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D017828:Rifabutin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D017320:HIV Protease Inhibitors; C107196:25-desacetylrifabutin; D017828:Rifabutin; D019469:Indinavir