Resztak Matylda, Sobiak Joanna, Czyrski Andrzej
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
Pharmaceutics. 2021 Nov 23;13(12):1991. doi: 10.3390/pharmaceutics13121991.
The review includes studies dated 2011-2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration-time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients' population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.
该综述纳入了2011年至2021年期间的研究，这些研究展示了关于儿童伏立康唑（VCZ）、霉酚酸（MPA）和万古霉素（VAN）治疗药物监测（TDM）的最新信息。通过提供药物药代动力学差异方面的信息，强调了儿科患者进行TDM的必要性。对于所有侵袭性真菌感染（IFI）的儿科患者，VCZ的TDM应是强制性的。VCZ药代动力学在患者间和患者内存在很大差异，这使得在该人群中治疗期间达到并维持治疗浓度具有挑战性。已证实的研究表明，在大多数情况下，尽管有更新的剂量建议，但VCZ血浆浓度仍低于治疗水平。只有重复进行TDM才能预测儿童抗真菌治疗中的药物暴露并实现个体化给药。在接受霉酚酸酯（MMF）治疗的儿童中，与成年患者类似，MMF活性形式MPA的TDM作用尚未得到充分确立，仍在持续争论中。关于MPA TDM的研究已在肾移植后的儿童、心脏、肝脏或肠道等其他器官移植后的儿童、造血干细胞移植或脐血移植后的儿童以及患有狼疮、肾病综合征、过敏性紫癜和其他自身免疫性疾病的儿童中开展。MPA TDM基于浓度-时间曲线下面积；然而，根据治疗指征，建议的值有所不同，并且还提出了其他方法，如药效学和药物遗传学生物标志物。VAN是一种杀菌剂，需要进行TDM以预防急性肾病。特定的患者群体是儿科患者。对于该群体，由于受试者之间消除率和分布容积发生变化，一般的给药建议可能无效。另一个因素是患者之间药物游离分数的变异性。这可能由患者群体和样本预处理共同导致。尽管VCZ、MMF和VAN已在儿科患者中应用多年，但在这些药物的TDM方面仍有一些问题需要解决，以确保安全有效的治疗。除了药代动力学方法外，药效学和药物遗传学在TDM中被更多地提出。
