Rich P, Scher R K, Breneman D, Savin R C, Feingold D S, Konnikov N, Shupack J L, Pinnell S, Levine N, Lowe N J, Aly R, Odom R B, Greer D L, Morman M R, Bucko A D, Tschen E H, Elewski B E, Smith E B, Hilbert J
Oregon Health Sciences University, Portland, USA.
J Am Acad Dermatol. 1998 Jun;38(6 Pt 2):S103-9. doi: 10.1016/s0190-9622(98)70493-1.
Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed.
The purpose of this study was to determine plasma and toenail concentrations of fluconazole.
In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued.
Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects.
Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.
初步临床数据表明氟康唑对甲癣患者的治疗有效。为了设计最佳给药方案，需要更好地了解氟康唑在指甲中的分布和清除情况。
本研究旨在测定氟康唑的血浆和趾甲浓度。
在这项多中心、随机、双盲研究中，每周一次给予甲癣患者氟康唑（150mg、300mg或450mg）或匹配的安慰剂，最长给药12个月。共有151名受试者参与了药代动力学评估。在基线、2周访视时、直至治疗结束的每月访视时以及氟康唑停药后的2、4和6个月（仅后两个月采集趾甲样本）采集血样以及患甲和健甲的远端趾甲剪片，用于测定氟康唑浓度。
几乎所有受试者在2周评估时在健甲和患甲中均检测到氟康唑。在三个氟康唑剂量组中，健甲中达到氟康唑稳态浓度的中位时间为4至5个月。在患甲中，氟康唑稳态浓度的达到更为缓慢，中位时间为6至7个月。在8个月评估时，患甲中氟康唑浓度高于相应的血浆氟康唑浓度，在三个活性治疗组中的比值为1.31至1.50。治疗停药后，趾甲中氟康唑浓度下降缓慢，150mg、300mg和450mg剂量的消除半衰期分别为2.5、2.4和3.7个月。大多数受试者在治疗后6个月时趾甲中仍存在可测量的氟康唑浓度。
氟康唑可迅速渗透到健甲和病甲中，在每周两次给药后产生可检测到的浓度。一旦渗透到指甲中，氟康唑在治疗停止后可维持长达6个月或更长时间。这些良好的药代动力学特征支持每周一次氟康唑给药方案用于治疗甲癣患者。
