Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands.
J Antimicrob Chemother. 2023 Dec 1;78(12):2886-2889. doi: 10.1093/jac/dkad324.
To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics.
In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily).
Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%.
This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction.
研究真实儿科患者群体中伊曲康唑的药代动力学，确认伊曲康唑的暴露量是否处于成人暴露范围之内。此外，我们首次描述了游离伊曲康唑的药代动力学。
在这项前瞻性观察性研究中，伊曲康唑的给药方案如下（静脉/口服/鼻胃管）：第 1 天和第 2 天，5.4mg/kg 伊曲康唑（最大剂量 200mg/次），每日 3 次，然后 5.4mg/kg 伊曲康唑（最大剂量 200mg/次），每日 1 次。至少评估了 1 个药代动力学曲线。采用非线性混合效应模型进行分析。使用上述维持剂量进行静脉给药和口服/鼻胃管给药的体重区间剂量方案进行蒙特卡罗模拟：I）<18kg（每日 100mg）；II）18-37kg（每日 150mg）；III）>37kg（每日 200mg）。
共评估了 17 名年龄中位数为 9 岁（范围 1-17 岁）、体重中位数为 26.0kg（范围 8.4-78.5kg）的儿科患者。描述游离浓度的线性药代动力学和可饱和蛋白结合的两室模型最适合伊曲康唑浓度。伊曲康唑的绝对生物利用度为 41.0%（95%CI：32.4%-50.8%）。静脉和口服/鼻胃管给药后总伊曲康唑浓度的模拟暴露（AUC0-24h，SS）中位数（IQR）分别为 87.7mg·h/L（70.5-105.1）和 50.3mg·h/L（39.0-62.4）。游离伊曲康唑分数（游离/总）范围为 0.5%-2.3%。
本研究揭示了经鼻胃管给药时胶囊打开后生物利用度较低。静脉给药后伊曲康唑的暴露量处于预期范围。报告了总伊曲康唑和游离伊曲康唑的药代动力学，游离分数范围为 5 倍。
