Division of Stem Cell Transplantation, Department of Pediatrics, Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, USA.
Clin Pharmacokinet. 2023 Jul;62(7):955-968. doi: 10.1007/s40262-023-01275-x. Epub 2023 Jul 6.
Busulfan is commonly used in the chemotherapy prior to hematopoietic cell transplantation (HCT). Busulfan has a narrow therapeutic window and a well-established exposure-response relationship with important clinical outcomes. Model-informed precision dosing (MIPD) based on population pharmacokinetic (popPK) models has been implemented in the clinical settings. We aimed to systematically review existing literature on popPK models of intravenous busulfan.
We systematically searched Ovid MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science databases from inception to December 2022 to identify original popPK models (nonlinear mixed-effect modeling) of intravenous busulfan in HCT population. Model-predicted busulfan clearance (CL) was compared using US population data.
Of the 44 eligible popPK studies published since 2002, 68% were developed predominantly in children, 20% in adults, and 11% in both children and adults. The majority of the models were described using first-order elimination or time-varying CL (69% and 26%, respectively). All but three included a body-size descriptor (e.g., body weight, body surface area). Other commonly included covariates were age (30%) and GSTA1 variant (15%). Median between-subject and between-occasion variabilities of CL were 20% and 11%, respectively. Between-model variabilities in predicted median CL were < 20% in all of the weight tiers (10-110 kg) in the simulation based on US population data.
Busulfan PK is commonly described using a first-order elimination or time-varying CL. A simple model with limited covariates were generally sufficient to attain relatively small unexplained variabilities. However, therapeutic drug monitoring may still be necessary to attain a narrow target exposure.
在造血细胞移植（HCT）前，白消安通常用于化疗。白消安的治疗窗较窄，与重要的临床结局有明确的暴露-反应关系。基于群体药代动力学（popPK）模型的模型指导下的精准给药（MIPD）已在临床环境中实施。我们旨在系统地回顾静脉用白消安的现有 popPK 模型文献。
我们系统地检索了 Ovid MEDLINE、EMBASE、Cochrane 图书馆、Scopus 和 Web of Science 数据库，从建库到 2022 年 12 月，以确定 HCT 人群中静脉用白消安的原始 popPK 模型（非线性混合效应建模）。使用美国人群数据比较模型预测的白消安清除率（CL）。
自 2002 年以来发表的 44 项符合条件的 popPK 研究中，68%主要在儿童中开发，20%在成人中开发，11%在儿童和成人中均有开发。大多数模型均采用一级消除或时变 CL 来描述（分别为 69%和 26%）。除了三个模型外，其余模型均包含一个体型描述符（例如体重、体表面积）。其他常见的协变量包括年龄（30%）和 GSTA1 变体（15%）。CL 的个体间和个体内变异性中位数分别为 20%和 11%。基于美国人群数据进行模拟，所有体重范围内（10-110kg）预测的中位 CL 之间的模型间变异性均小于 20%。
白消安 PK 通常采用一级消除或时变 CL 来描述。通常，具有有限协变量的简单模型足以获得相对较小的未解释变异性。然而，为了达到狭窄的目标暴露，可能仍需要进行治疗药物监测。
