Institute of Pharmaceutical and Medical Chemistry - Department of Clinical Pharmacy, Westphalian Wilhelms University Münster, Münster, Germany.
Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, Children's University Hospital Münster, Münster, Germany.
Mycoses. 2023 Nov;66(11):969-976. doi: 10.1111/myc.13643. Epub 2023 Aug 8.
Voriconazole (VCZ) is an important first-line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1-138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01-16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1-6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.
伏立康唑（VCZ）是治疗侵袭性真菌感染的重要一线选择，已批准用于 24 个月以上的儿科患者，剂量方案不同，考虑到不同的发育阶段。<24 个月儿童的剂量和暴露信息很少。在这里，我们报告了我们在<24 个月因缺乏替代治疗方案而接受 VCZ 治疗的儿童的经验。这项回顾性分析包括 17 名免疫功能低下的儿童，年龄在 3 至<24 个月之间，共有 50 个不同的治疗发作，他们在 2004 年至 2022 年期间因预防（14 名患者；47 个发作）或因禁忌、不耐受或缺乏替代选择而接受口服（46 个发作）或静脉内（4 个发作）VCZ 作为经验性治疗。根据临床需要测量谷浓度，根据肝功能参数和因不良事件（AE）而停药来评估耐受性。VCZ 的中位治疗时间为 10 天（范围：1-138）。静脉内剂量范围为 4.9 至 7.0mg/kg（中位数：6.5），每日两次，口服剂量范围为 3.8 至 29mg/kg（中位数：9.5），每日两次。中位谷浓度为 0.63mg/L（范围：0.01-16.2；38 个样本）。仅 34.2%的样本处于推荐的 1-6mg/L 目标范围；57.9%的样本浓度较低，7.9%的样本浓度较高。在 VCZ 治疗期间，治疗前、治疗期间和治疗结束时分析的肝功能参数没有显示出明显的变化。剂量与暴露或肝功能参数之间没有相关性。在三个发作中，由于 AE（6%；3 名患者）而停用 VCZ。总之，这项回顾性分析没有显示出<24 个月儿童毒性增加的信号。经验性给药导致大部分治疗效果不佳，这强调了在该年龄组中更系统地研究 VCZ 药代动力学的必要性。
