Effects of itraconazole or grapefruit juice on the pharmacokinetics of telithromycin.
OBJECTIVE
To determine whether coadministration of the cytochrome P450 3A4 (CYP3A4) inhibitors itraconazole or grapefruit juice will modify the pharmacokinetic profile of telithromycin, and to assess the safety of telithromycin.


METHODS
Two single-center, open-label studies; the itraconazole study was nonrandomized, sequential, and multiple dose, and the grapefruit juice study was randomized, two-period crossover, and single dose.


METHODS
Two clinical investigative centers in the United States.


METHODS
Thirty-four healthy, nonsmoking male volunteers aged 18-45 years.


METHODS
All patients received telithromycin 800 mg/day; 18 patients received concomitant itraconazole 200 mg/day, and 16 received concomitant single-dose, single-strength grapefruit juice.


RESULTS
Standard pharmacokinetic and safety measurements were performed. Itraconazole given concomitantly with telithromycin increased the steady-state area under the plasma concentration-time curve from 0-24 hours of telithromycin by 53.8% (p<0.0001). Coadministration of grapefruit juice did not affect telithromycin pharmacokinetic parameters, and telithromycin was well tolerated in both studies.


CONCLUSIONS
Only modest changes in the pharmacokinetics of telithromycin were seen with concomitant administration of itraconazole. Telithromycin pharmacokinetics were unaffected by concomitant administration of grapefruit juice.
Shi
Jun
J
Global Biopharmaceutics and Clinical Pharmacokinetics, Aventis Pharmaceuticals, Bridgewater, New Jersey 08807-0800, USA. Jun.Shi@aventis.com
Montay
Guy
G
Leroy
Bruno
B
Bhargava
Vijay O
VO
D000284:Administration, Oral; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D001628:Beverages; D001663:Bilirubin / Q000097:blood; D032083:Citrus paradisi / Q000737:chemistry*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects / Q000379:methods; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D048628:Ketolides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D018942:Macrolides / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D013607:Tablets
D065607:Cytochrome P-450 Enzyme Inhibitors; D048628:Ketolides; D018942:Macrolides; C419366:RU 76363; D013607:Tablets; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C106791:telithromycin; D001663:Bilirubin