Purkins Lynn, Wood Nolan, Greenhalgh Katie, Allen Michael J, Oliver Stuart D
Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK.
Br J Clin Pharmacol. 2003 Dec;56 Suppl 1(Suppl 1):10-6. doi: 10.1046/j.1365-2125.2003.01993.x.
Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing.
Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg-1 twice daily, 4 mg kg-1 once daily, 2 mg kg-1 three times daily, or 3 mg kg-1 twice daily. Eleven subjects received 1.5 mg kg-1 three times daily, and 21 subjects were administered placebo.
Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCtau. The absorption of voriconazole was rapid (mean tmax= 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after tmax was generally biphasic. By day 12, the Cmax, AUCtau, tmax, and t1/2 values for the 3 mg kg-1 twice-daily group were 2356 ng ml-1, 11 170 ng.h ml-1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCtau, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg-1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCtau values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 micro g ml-1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing.
The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg-1 twice daily.
伏立康唑是一种新型强效三唑类药物，对临床上重要的和新出现的病原体具有广谱抗真菌活性。本研究评估了单次和多次给药后口服伏立康唑的安全性、耐受性和药代动力学。
64名健康受试者被随机分组接受治疗，56名完成了研究。每组8名受试者分别接受每日两次2mg/kg的伏立康唑剂量、每日一次4mg/kg、每日三次2mg/kg或每日两次3mg/kg的剂量。11名受试者接受每日三次1.5mg/kg的剂量，21名受试者服用安慰剂。
伏立康唑表现出非线性（剂量和时间依赖性）药代动力学。多次给药时线性比>1且kel值降低，终末相t1/2随之增加，证实了这种与线性药代动力学的偏差。Cmax和AUCtau也存在显著的个体间差异。单次和多次给药后伏立康唑吸收迅速（平均tmax = 0.9 - 1.7小时），tmax后血浆浓度-时间曲线的下降通常呈双相。到第12天，每日两次3mg/kg组的Cmax、AUCtau、tmax和t1/2值分别为2356ng/ml、11170ng·h/ml、1.1小时和6.4小时。多次给药后观察到的伏立康唑蓄积大于单剂量数据预测值。每日两次给予3mg/kg伏立康唑组的Cmax和AUCtau蓄积率分别为1.97和3.55，不同治疗组间有所不同，似乎受每日总剂量、给药频率和持续时间影响。对Cmin值的直观检查以及对Cmax和AUCtau值的统计分析表明，多次给药的第五至第六天达到稳态水平。伏立康唑的血浆浓度远高于曲霉属、念珠菌属以及大多数新出现真菌病原体的最低抑菌浓度（Cmin>0.8μg/ml）。伏立康唑耐受性良好：大多数与治疗相关的不良事件（视力异常、头痛、头晕）较轻，给药后1小时内缓解。
基于这些结果，为后续II/III期临床试验选择的口服给药方案为每日两次200mg，相当于每日两次给予3mg/kg。
