Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects.
OBJECTIVE
The primary objective of this interaction study was to confirm preclinical data suggesting that moxifloxacin is not metabolized by CYP 450 isozymes. Itraconazole, a strong CYP 3A4 inhibitor, was used as comedication.


METHODS
Twelve healthy male subjects were enrolled in this randomized study using 400 mg of oral moxifloxacin (MXF) administered alone and on the 7th day of a 9-day treatment regimen with itraconazole (ITR) 200 mg p.o., o.d. In addition to the assessment of safety and tolerability, non-compartmental pharmacokinetics of moxifloxacin, itraconazole and their respective metabolites were analyzed using plasma concentrations obtained using HPLC.


RESULTS
All treatment regimens were safe and well-tolerated. No interaction with itraconazole was observed for moxifloxacin (relative bioavailability: 111.6% (90% CI 106.5 to 117.0%), C(max) ratio: 103.7% (84.8-126.9%) and its sulfometabolite (Ml) (AUC ratio: 107.7% (95.6, 121.4%), C(max) ratio: 105.8% (89.9-124.5%)). There was a 30% decrease in AUC with M2 moxifloxacin metabolite (glucuronide) accompanied by an approximately 54% increase in renal excretion, which may be due to changes in phase 2 metabolism and/or transport mechanisms altered by itraconazole. Exposure (AUC) to itraconazole and its hydroxymetabolite were marginally altered by moxifloxacin (AUC +5% for itraconazole and -5% for hydroxy-itraconazole (OH-ITR)) indicating the absence of a clinically relevant influence of moxifloxacin on itraconazole. Mean peak concentrations in plasma (C(max)) were reduced for ITR and OH-ITR by approximately 14% and 18%, respectively, when administered concomitantly with moxifloxacin. This was attributed to the sensitivity of itraconazole absorption to changes in gastric physiology (pH, gastric transit, administration after fasting) and was deemed as clinically irrelevant.


CONCLUSIONS
Results of this study indicate that moxifloxacin is not a substrate for CYP 450 3A4 isozymes confirming previous preclinical in vitro data. Moxifloxacin can therefore be safely coadministered with CYP 3A4 inhibitors without the need for dose adjustment. No clinically relevant changes in the pharmacokinetics of itraconazole were observed during the study.
Stass
H
H
Clinical Pharmacology, Bayer AG, Wuppertal, Germany. Heino.Stass.hs@bayer-ag.de
Nagelschmitz
J
J
Moeller
J G
JG
Delesen
H
H
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005215:Fasting; D024841:Fluoroquinolones; D005858:Germany; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; C084794:hydroxyitraconazole; D017964:Itraconazole; D000077266:Moxifloxacin