Chamzas Athanasios, Tellez Eglis, SyBing Andrew, Gobburu Jogarao V S, Gopalakrishnan Mathangi
Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD, United States.
Providence St Joseph, Eureka, CA, United States.
Front Pharmacol. 2024 Sep 19;15:1443988. doi: 10.3389/fphar.2024.1443988. eCollection 2024.
Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12 ng/mL at the earliest.
Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated.
The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7 L/h for a typical patient weighing 70 kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1 mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12 ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment.
Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.
他克莫司是一种用于预防肾移植患者器官排斥反应的免疫抑制剂，患者间存在高度变异性，因此需要进行治疗药物监测。西班牙裔患者移植后早期的他克莫司暴露情况研究较少。尽管基因型信息与药代动力学差异相关，但其临床应用仍然有限。本研究旨在采用基于真实世界数据驱动的、药代动力学模型的方法，针对西班牙裔患者的他克莫司，通过模拟确定合适的初始剂量，并设计最佳剂量滴定策略，以尽早达到10 - 12 ng/mL的血浆谷浓度目标水平。
从肾移植后自我认定为西班牙裔受试者的电子病历中获取他克莫司的稀疏浓度-时间数据。利用丰富的药代动力学文献数据估计结构药代动力学模型参数，然后在当前分析中固定这些参数。仅用他克莫司的稀疏数据估计表观清除率，并确定潜在的协变量。然后评估各种起始剂量和不同剂量滴定策略的模拟情况。
分析纳入了121例肾移植患者，共2215个他克莫司谷浓度。一个具有按体重比例缩放和根据表观清除率随时间变化的血细胞比容的二室转运吸收模型充分描述了数据。对于一名体重7０kg且血细胞比容为30%的典型患者，估计的表观清除率为13.7 L/h，与其他患者群体相比，清除率降低了40%。基于模型的模拟表明，西班牙裔人群的最佳初始剂量为0.1 mg/kg/天。所提出的滴定策略基于他克莫司的谷浓度进行三次剂量调整，在治疗第一周后，使目标范围内（10 - 12 ng/mL）的患者比例增加了2.5倍以上，并使治疗窗以外的患者比例降低了50%。
与其他具有相似特征的人群相比，西班牙裔肾移植人群中典型患者的表观清除率估计降低了40%。所提出的剂量调整能够快速且安全地达到目标范围。本研究提倡基于群体药代动力学制定个性化的他克莫司给药方案，以优化西班牙裔肾移植受者的治疗。
