Continuous and intermittent itraconazole dosing schedules for the treatment of onychomycosis: a pharmacokinetic comparison

This multicentre, double-blind, randomized study compared the pharmacokinet ics of itraconazole given at 200 mg once daily for 3 months and intermitten tly at 200 mg twice daily for 1 week per month followed by a 3-week drug-fr ee period for 3 months in the treatment of onychomycosis. Patients were fol lowed for 9 months after treatment. Itraconazole and hydroxy-itraconazole p lasma concentrations and itraconazole nail tip concentrations were determin ed at regular intervals, With intermittent therapy (n = 64), increases of c onsistent magnitude were seen in the mean itraconazole and hydroxy-itracona zole plasma concentrations at the end of each 1-week treatment phase; value s returned towards baseline during each subsequent 3-week drug-free period. The mean concentration of itraconazole in fingernail tips increased steadi ly from week 4, reached a maximum value at week 24 (213 ng/g), declined sha rply between weeks 24 and 36 and returned to baseline by week 48; the mean concentration profile was similar for toenail tips (maximum value 305 ng/g at week 24) but decreased at a slower rate. With continuous therapy (n = 65 ), steady-state mean plasma concentrations of itraconazole and hydroxy-itra conazole were obtained within 4-5 weeks of the start of treatment and remai ned reasonably constant between weeks 4 and 12. The mean concentration of i traconazole in fingernail tips reached a maximum value at week 12 (524 ng/g ) and returned towards baseline by week 48: in contrast, the maximum mean c oncentration of itraconazole in toenail tips was 698 ng/g at week 36 and di d not return to baseline by week 48. No clear relationship was observed bet ween response to treatment and concentration of itraconazole or hydroxy-itr aconazole in plasma or itraconazole in nails, suggesting that concentration s exceeded therapeutic levels. In conclusion, intermittent therapy resulted in higher maximum itraconazole plasma concentrations but lower total drug exposure, and hence lower itraconazole nail concentrations, than continuous therapy. However, the intermittent schedule was not associated with a lowe r cure rate, which indicates that itraconazole nail concentrations remained within the therapeutic range.