Introduction

Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients.

Methods

The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles.

Results

The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity.

Conclusions

A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.

中文翻译：

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使用群体建模和模拟的新肾移植患者 Envarsus 的治疗药物监测策略

介绍

他克莫司是移植免疫抑制的基石，是一种治疗指数窄的药物，具有低且高度可变的生物利用度。基于谷水平评估的治疗药物监测是强制性的，以针对个性化暴露并避免排斥和毒性。群体药代动力学 (POPPK) 模型可能是一种有用的工具，可通过指导初始剂量直至达到稳定状态并且可以可靠地将谷水平用作暴露的替代标志物来改善早期达到目标范围。在这里，我们提出了第一个 POPPK，用于预测成人肾脏受者中每日一次缓释他克莫司 (LCPT) 的初始剂量。

方法

该模型是利用最近一项药代动力学随机临床研究的数据开发的，其中 69 名新肾受者（其中 33 名接受 LCPT 治疗）接受了他克莫司的强化血液采样策略，包括四个完整的药代动力学特征。

结果

三相模型很好地描述了 LCPT 的复杂和长期吸收，该模型将体重和 CYP3A5 基因型作为重要的协变量，占患者间变异性的很大一部分：特别是，CYP3A5*1/*3表达者具有LCPT 清除率提高 66%。然后，我们通过模拟生成了基于模型的个性化给药策略，该策略可以通过将目标范围内的患者比例几乎翻倍（69.3% 与标准基于体重的方法的 36.1% 相比）来提高早期达到治疗谷值水平在移植后第 4 天，显着降低有毒性风险的过度暴露患者的比例。

结论

一个 POPPK 模型已成功开发用于新肾受者的 LCPT。该模型可以在移植后早期指导个性化给药策略。对于要转化为临床实践的模型，其早期达到治疗谷水平的有益影响应在进一步研究中证明对硬临床结果的影响。