Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany; Department of Clinical Pharmacy, Institute of Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany; Graduate Research Training Program PharMetrX, Germany.
Eur J Pharm Sci. 2019 Apr 1;131:218-229. doi: 10.1016/j.ejps.2019.02.001. Epub 2019 Feb 4.
Voriconazole, a broad-spectrum antifungal drug used to prevent and treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by various CYP enzymes. An adequate unbound antibiotic concentration-time profile at the target-site of an infection is crucial for effective prophylaxis or therapy success. Therefore, the aim was to evaluate the pharmacokinetics of voriconazole after the approved sequence dosing in healthy volunteers in interstitial space fluid, assessed by microdialysis, and in plasma. Moreover, potential pharmacogenetic influences of CYP2C19 polymorphisms on pharmacokinetics were investigated. The prospective, open-labelled, uncontrolled long-term microdialysis study included 9 healthy male individuals receiving the approved sequence dosing regimen for voriconazole. Unbound voriconazole concentrations were sampled over 84 h in interstitial space fluid of subcutaneous adipose tissue and in plasma and subsequently quantified via high-performance liquid chromatography. For pharmacokinetic data analysis, non-compartmental analysis was used. High interindividual variability in voriconazole concentration-time profiles was detected although dosing was adapted to body weight for the first intravenous administrations. Due to nonlinear pharmacokinetics, target-site exposure of voriconazole in healthy volunteers was found to be highly comparable to plasma exposure, particularly after multiple dosing. Regarding the CYP2C19 genotype-predicted phenotype, the individuals revealed a broad spectrum, ranging from poor to rapid metaboliser status. A strong relation between CYP2C19 genotype-predicted phenotype and voriconazole clearance was identified.
伏立康唑是一种广谱抗真菌药物，用于预防和治疗侵袭性真菌感染，具有复杂的药代动力学特性，主要通过多种 CYP 酶代谢。在感染的靶部位获得足够的游离抗生素浓度-时间曲线下面积对于有效的预防或治疗成功至关重要。因此，本研究旨在通过微透析评估健康志愿者中伏立康唑在间质液中的药代动力学，并用血浆进行评估。此外，还研究了 CYP2C19 多态性对药代动力学的潜在遗传影响。这项前瞻性、开放标签、非对照的长期微透析研究纳入了 9 名接受批准的伏立康唑序贯给药方案的健康男性志愿者。在皮下脂肪组织的间质液和血浆中，在 84 小时内采样未结合的伏立康唑浓度，并通过高效液相色谱法进行定量。采用非房室分析进行药代动力学数据分析。尽管首次静脉给药时根据体重调整了剂量，但仍检测到伏立康唑浓度-时间曲线下面积的个体间变异性很大。由于药代动力学呈非线性，因此在健康志愿者中，伏立康唑的靶部位暴露与血浆暴露高度相似，尤其是在多次给药后。关于 CYP2C19 基因型预测表型，个体表现出广泛的范围，从代谢不良到快速代谢者。还确定了 CYP2C19 基因型预测表型与伏立康唑清除率之间的强烈关系。
