Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
Center of Expertise in Mycology, Radboud University Medical Center/Canisius Wilhelmina Ziekenhuis, Nijmegen, The Netherlands.
J Antimicrob Chemother. 2023 May 3;78(5):1219-1224. doi: 10.1093/jac/dkad072.
To describe itraconazole and hydroxy-itraconazole pharmacokinetics following intravenous (IV) administration of a previously developed nanocrystal formulation (NCF) in haematopoietic cell transplant (HCT) recipients for prophylaxis of invasive fungal disease.
In a prospective Phase II study, 10 HCT recipients received itraconazole NCF administered in 2-hour infusions of 200 mg twice daily for 2 days, followed by 200 mg once daily until Day 14. Full pharmacokinetic curves were obtained on Days 7 and 14. Additional samples were collected pre- and post-infusion until Day 6, pre-infusion on Days 10 and 12, and during washout on Days 16, 17, 18, 19 and 28. Itraconazole and hydroxy-itraconazole pharmacokinetics were analysed by non-linear mixed-effects population pharmacokinetic modelling.
Four-hundred and seventy-one itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. Data were best described by a semi-mechanistic model with central and peripheral itraconazole compartments and a hydroxy-itraconazole compartment with dissolution of itraconazole drug particles from nanocrystals and first-order distribution and elimination. The final model included interindividual variability on itraconazole clearance and hydroxy-itraconazole clearance.
This study provides information on the pharmacokinetic properties of the itraconazole NCF useful for development of this formulation. Our results suggest that itraconazole NCF is a suitable formulation and may warrant renewal in the setting of repurposing. Our findings may be useful for the reformulation of other highly lipophilic compounds as well.
描述先前开发的纳米晶体制剂（NCF）在接受造血细胞移植（HCT）的患者中进行静脉（IV）给药后，伊曲康唑和羟基伊曲康唑的药代动力学，以预防侵袭性真菌感染。
在一项前瞻性的 II 期研究中，10 名 HCT 受者接受伊曲康唑 NCF 治疗，2 小时输注 200mg，每日 2 次，持续 2 天，然后每日 200mg 直至第 14 天。在第 7 天和第 14 天获得完整的药代动力学曲线。在第 6 天之前和输注后，第 10 天和第 12 天的预输注，以及在第 16、17、18、19 和 28 天的洗脱期收集额外的样本。通过非线性混合效应群体药代动力学模型分析伊曲康唑和羟基伊曲康唑的药代动力学。
纳入了来自 10 名患者的 471 个伊曲康唑和 471 对羟基伊曲康唑浓度进行分析。数据最好通过一个半机械模型来描述，该模型具有中央和外周伊曲康唑隔室，以及一个羟基伊曲康唑隔室，其中包括伊曲康唑药物颗粒从纳米晶体中的溶解以及一级分布和消除。最终模型包括伊曲康唑清除率和羟基伊曲康唑清除率的个体间变异性。
本研究提供了有关伊曲康唑 NCF 的药代动力学特性的信息，这对该制剂的开发很有用。我们的结果表明，伊曲康唑 NCF 是一种合适的制剂，可能有必要在重新利用的情况下进行更新。我们的发现也可能对其他高度亲脂性化合物的重新配方有用。
