Optimizing Dose Conversion from IR-Tac to LCP-Tac Formulations in Renal Transplant Recipients: A Population Pharmacokinetic Modeling Study.

IF 5.5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Zeyar Mohammed Ali, Beatriz Fernández-Alarcón, Pere Fontova, Anna Vidal-Alabró, Raul Rigo-Bonnin, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alexandre Favà, Josep M Grinyó, Josep M Cruzado, Helena Colom, Nuria Lloberas
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引用次数: 0

Abstract

Background/Objectives: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. Methods: A PopPK model was developed in NONMEM using full PK profiles (10-18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. Results: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. CYP3A5*1 expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for CYP3A5*1 expressers and 1:0.7 for non-expressers. Conclusions: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac's enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. These genotype-specific recommendations provide clinically actionable guidance to complement therapeutic drug monitoring and support more individualized conversion protocols in renal transplantation.

肾移植受者从IR-Tac到LCP-Tac的最佳剂量转换:群体药代动力学模型研究。
背景/目的:他克莫司的剂量仍然具有挑战性,因为其狭窄的治疗指数和高度的患者间和患者内部变异性。缓释每日一次的他克莫司(LCP-Tac)制剂与速释每日两次的他克莫司(IR-Tac)制剂相比,提供了更高的生物利用度和持续的药代动力学特征。虽然在配方之间切换时广泛推荐的一般转换比率为1:7 . 0,但目前的指南并未考虑药物遗传变异性。本研究旨在通过群体药代动力学(PopPK)模型确定CYP3A5基因型是否影响高加索肾移植受者的转换率。方法:在NONMEM中建立PopPK模型,使用来自30名同时接受IR-Tac和LCP-Tac治疗的稳定肾移植患者的完整PK谱(每个患者10-18个样本)。结果:他克莫司的药代动力学最好地描述为二阶吸收和线性消除的双室模型,每种制剂的吸收速率常数和滞后时间不同。在IR-Tac的表观清除率(CL/F)和Ka中加入昼夜节律显著改善了模型。CYP3A5多态性是解释CL/F变异最有力的协变量。CYP3A5*1表达者在转化为LCP-Tac后表现出更高的清除率和更低的暴露,需要更明显的剂量减少。模拟结果表明,CYP3A5*1表达者的最佳转化率为1:0.6,非表达者的最佳转化率为1:0.7。结论:这些发现强调需要超越一刀切的转化率,并采用基因型知情策略。LCP-Tac的增强生物利用度需要减少剂量,当从IR-Tac切换时,表达物的剂量更大。这些基因型特异性建议提供了临床可行的指导,以补充治疗性药物监测,并支持肾移植中更个性化的转换方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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