Department of Paediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France.
Service of Pharmacy, Centre Hospitalier Intercommunal Nord Ardennes, Charleville-Mézières, France.
Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0159722. doi: 10.1128/aac.01597-22. Epub 2023 Mar 7.
Valganciclovir, the ganciclovir prodrug, is an antiviral agent used to prevent cytomegalovirus infection in renal transplant children. Therapeutic drug monitoring is still necessary to ensure optimal therapeutic area under the concentration-time curve from 0 to 24 h (AUC) of 40 to 60 μg·h/mL since valganciclovir presents a high pharmacokinetic variability. To calculate ganciclovir AUC with the trapezoidal method, 7 samples are needed. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy (LSS) for individualizing valganciclovir dose in renal transplant children. Rich pharmacokinetic data from ganciclovir plasmatic dosages measured in renal transplant children who received valganciclovir to prevent cytomegalovirus infection at Robert Debré University Hospital were collected retrospectively. Ganciclovir AUCs were calculated using the trapezoidal method. The LSS was developed using a multilinear regression approach to predict AUC. The patients included were divided into two groups for model development (50 patients) and validation (30 patients). A total of 80 patients were included between February 2005 and November 2018. Multilinear regression models were developed on 50 pharmacokinetic profiles (50 patients) and validated with an independent group of 43 pharmacokinetic profiles (30 patients). Regressions based on samples collected at T1h-T4h-T8h, T2h-T4h-T8h, or T1h-T2h-T8h presented the best AUC predictive performances with an average difference between reference and predicted AUC of -0.27, 0.34, and -0.40 μg·h/mL, respectively. In conclusion, valganciclovir dosage adaptation was required in children to achieve the target AUC. Three LSS models using three pharmacokinetic blood samples instead of seven will be useful for individualizing valganciclovir prophylaxis in renal transplant children.
缬更昔洛韦，更昔洛韦前体药物，是一种抗病毒药物，用于预防肾移植儿童的巨细胞病毒感染。由于缬更昔洛韦的药代动力学变异性很大，仍需要进行治疗药物监测，以确保 0 至 24 小时浓度-时间曲线下面积（AUC）达到 40 至 60μg·h/mL 的最佳治疗范围。使用梯形法计算更昔洛韦 AUC 需要 7 个样本。本研究的目的是开发和验证一种可靠且适用于临床的有限采样策略（LSS），以个体化肾移植儿童的缬更昔洛韦剂量。本研究回顾性收集了在罗伯特·德布雷大学医院接受缬更昔洛韦预防巨细胞病毒感染的肾移植儿童的更昔洛韦血浆剂量的丰富药代动力学数据。使用梯形法计算更昔洛韦 AUC。使用多线性回归方法来预测 AUC 来开发 LSS。将患者分为两组用于模型开发（50 例）和验证（30 例）。共有 80 例患者纳入 2005 年 2 月至 2018 年 11 月。在 50 个药代动力学图谱（50 例患者）上建立了多线性回归模型，并在 43 个独立的药代动力学图谱（30 例患者）上进行了验证。基于 T1h-T4h-T8h、T2h-T4h-T8h 或 T1h-T2h-T8h 采集样本的回归模型具有最佳的 AUC 预测性能，参考 AUC 与预测 AUC 的平均差值分别为-0.27、0.34 和-0.40μg·h/mL。总之，需要调整儿童的缬更昔洛韦剂量以达到目标 AUC。使用三个药代动力学血样而不是七个血样的三个 LSS 模型将有助于个体化肾移植儿童的缬更昔洛韦预防。
