Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers.
BACKGROUND
Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir.


METHODS
Sixteen healthy volunteers were administered a single oral dose of 1,000 mg mebendazole or 400 mg albendazole (2 x n = 8). AUC, C(max), and t(1/2) of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg bid.


RESULTS
Pharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC(0-24) (27 and 43% of baseline for albendazole and mebendazole, respectively) and C(max) (26 and 41% of baseline, respectively).


CONCLUSIONS
The AUC(0-24) of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitors.
Corti
Natascia
N
Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. natascia.corti@usz.ch
Heck
Antje
A
Rentsch
Katharina
K
Zingg
Walter
W
Jetter
Alexander
A
Stieger
Bruno
B
Pauli-Magnus
Christiane
C
D000328:Adult; D015766:Albendazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019380:Anti-HIV Agents / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008463:Mebendazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D012016:Reference Values; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D019380:Anti-HIV Agents; D000977:Antiparasitic Agents; D017320:HIV Protease Inhibitors; D008463:Mebendazole; D015766:Albendazole; D019438:Ritonavir