Havu V, Brandt H, Heikkilä H, Hollmen A, Oksman R, Rantanen T, Saari S, Stubb S, Turjanmaa K, Piepponen T
Turku University Central Hospital and Lääkäriasema Pulssi, Kiinamyllynkatu 8, FIN-20520, Turku, Finland.
Br J Dermatol. 1999 Jan;140(1):96-101. doi: 10.1046/j.1365-2133.1999.02614.x.
This multicentre, double-blind, randomized study compared the pharmacokinetics of itraconazole given at 200 mg once daily for 3 months and intermittently at 200 mg twice daily for 1 week per month followed by a 3-week drug-free period for 3 months in the treatment of onychomycosis. Patients were followed for 9 months after treatment. Itraconazole and hydroxy-itraconazole plasma concentrations and itraconazole nail tip concentrations were determined at regular intervals. With intermittent therapy (n = 64), increases of consistent magnitude were seen in the mean itraconazole and hydroxy-itraconazole plasma concentrations at the end of each 1-week treatment phase; values returned towards baseline during each subsequent 3-week drug-free period. The mean concentration of itraconazole in fingernail tips increased steadily from week 4, reached a maximum value at week 24 (213 ng/g), declined sharply 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-itraconazole were obtained within 4-5 weeks of the start of treatment and remained reasonably constant between weeks 4 and 12. The mean concentration of itraconazole 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 concentration of itraconazole in toenail tips was 698 ng/g at week 36 and did not return to baseline by week 48. No clear relationship was observed between response to treatment and concentration of itraconazole or hydroxy-itraconazole in plasma or itraconazole in nails, suggesting that concentrations 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 lower cure rate, which indicates that itraconazole nail concentrations remained within the therapeutic range.
这项多中心、双盲、随机研究比较了伊曲康唑治疗甲真菌病的药代动力学。治疗方案为：每日一次给予200mg伊曲康唑，持续3个月；或每月间歇性给药，每日两次，每次200mg，给药1周，随后停药3周，共3个月。治疗后对患者随访9个月。定期测定伊曲康唑和羟基伊曲康唑的血浆浓度以及伊曲康唑的指甲尖浓度。采用间歇性治疗（n = 64）时，在每个1周治疗阶段结束时，伊曲康唑和羟基伊曲康唑的平均血浆浓度出现一致幅度的升高；在随后的每个3周停药期，浓度恢复至基线水平。指甲尖中伊曲康唑的平均浓度从第4周开始稳步上升，在第24周达到最大值（213 ng/g），在第24周和第36周之间急剧下降，到第48周恢复至基线水平；趾甲尖的平均浓度曲线相似（第24周最大值为305 ng/g），但下降速度较慢。采用持续治疗（n = 65）时，治疗开始后4 - 5周内获得伊曲康唑和羟基伊曲康唑的稳态平均血浆浓度，在第4周和第12周之间保持相对稳定。指甲尖中伊曲康唑的平均浓度在第12周达到最大值（524 ng/g），到第48周恢复至基线水平；相比之下，趾甲尖中伊曲康唑的最大平均浓度在第36周为698 ng/g，到第48周未恢复至基线水平。未观察到治疗反应与血浆中伊曲康唑或羟基伊曲康唑浓度以及指甲中伊曲康唑浓度之间存在明确关系，这表明浓度超过了治疗水平。总之，与持续治疗相比，间歇性治疗导致伊曲康唑血浆浓度的最大值更高，但总药物暴露量更低，因此伊曲康唑的指甲浓度也更低。然而，间歇性给药方案与较低的治愈率无关，这表明伊曲康唑的指甲浓度仍在治疗范围内。
