成人异基因造血细胞移植受者的他克莫司群体药代动力学模型为精准给药提供了临床机遇。
A Tacrolimus Population Pharmacokinetic Model for Adult Allogeneic Hematopoietic Cell Transplant Recipients Provides Clinical Opportunities for Precision Dosing.
作者信息
Dunlap Tyler C, Zhu Jing, Weiner Daniel L, Kemper Ryan M, DeVane Susanna C, Ma Feiyun, Nguyen Veronica, Coghill James M, Dang Viet, Grgic Tatjana, Jamieson Katarzyna, Miller Jordan, Myers Jennifer, Patel Tejendra, Riches Marcie, Serody Jonathan S, Trepte Morgan, Vincent Benjamin G, Wood William A, Ptachcinski Jonathan R, Shaw J Ryan, Weimer Eric, Armistead Paul M, Crona Daniel J
机构信息
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
Bone Marrow Transplant and Cellular Therapy Program, University of North Carolina Medical Center, Chapel Hill, NC, USA.
出版信息
Clin Pharmacokinet. 2025 Aug 12. doi: 10.1007/s40262-025-01529-w.
BACKGROUND
Tacrolimus is a cornerstone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplant (allo-HCT) recipients. However, a narrow therapeutic index and high interindividual variability in pharmacokinetics (PK) make starting dose selection a major challenge in clinical practice.
METHODS
Data from two PK studies conducted at the University of North Carolina Medical Center (UNCMC) were used to develop an oral tacrolimus population pharmacokinetic (popPK) model specific to adult allo-HCT recipients. Monte Carlo simulations were performed to compare the likelihood of achieving the UNCMC institutional target trough concentration range (ITR) (5-10 ng/mL) on the day of transplant (D0) under the current institutional dosing protocol, dosing recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC), and model-derived dosing recommendations.
RESULTS
In total, 290 allo-HCT recipients contributed a total of 906 PK samples to the final analysis. A two-compartment popPK model adequately described the PK data. Population typical values of apparent clearance (TVCL/F) for 70 kg individuals receiving reduced intensity conditioning were 0.33 L/h/kg for CYP3A5 poor metabolizers (PMs) and 0.70 L/h/kg for intermediate and normal metabolizers (IMs and NMs). The probability of the population-level average D0 trough concentration being within the UNCMC ITR under the current UNCMC weight-based dosing protocol, CPIC-based, and model-derived dosing strategies were estimated to be 37%, 45%, and 76%, respectively. CYP3A5 IMs and NMs were predicted to require a 100% dose increase relative to CYP3A5 PMs.
CONCLUSIONS
We propose a new oral tacrolimus dosing strategy for adult allo-HCT recipients, which suggests the current weight-based dosing paradigm is insufficient. This new strategy includes CYP3A5 metabolizer phenotypes and conditioning regimen intensity, and could increase the percentage of allo-HCT recipients achieving target concentrations on D0.
CLINICAL TRIAL REGISTRATION NUMBER
Clinicaltrials.gov NCT04645667.
背景
他克莫司是异基因造血细胞移植（allo-HCT）受者急性移植物抗宿主病（aGVHD）预防的基石。然而，治疗指数狭窄和药代动力学（PK）个体间差异大使得起始剂量选择成为临床实践中的一项重大挑战。
方法
利用在北卡罗来纳大学医学中心（UNCMC）进行的两项PK研究的数据，建立了一个针对成年allo-HCT受者的口服他克莫司群体药代动力学（popPK）模型。进行蒙特卡洛模拟，以比较在当前机构给药方案、临床药物基因组学实施联盟（CPIC）的给药建议以及模型推导的给药建议下，移植当天（D0）达到UNCMC机构目标谷浓度范围（ITR）（5-10 ng/mL）的可能性。
结果
共有290名allo-HCT受者为最终分析贡献了906个PK样本。一个二室popPK模型充分描述了PK数据。接受减低强度预处理的70 kg个体的表观清除率（TVCL/F）的群体典型值，对于CYP3A5慢代谢者（PMs）为0.33 L/h/kg，对于中间代谢者和正常代谢者（IMs和NMs）为0.70 L/h/kg。在当前基于UNCMC体重的给药方案、基于CPIC的给药方案和模型推导的给药策略下，群体水平平均D0谷浓度在UNCMC ITR范围内的概率分别估计为37%、45%和76%。预计CYP3A5 IMs和NMs相对于CYP3A5 PMs需要增加100%的剂量。
结论
我们为成年allo-HCT受者提出了一种新的口服他克莫司给药策略，表明当前基于体重的给药模式是不够的。这种新策略包括CYP3A5代谢表型和预处理方案强度，并可能增加在D0达到目标浓度的allo-HCT受者的比例。
临床试验注册号
Clinicaltrials.gov NCT04645667。
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