Prediction of Tacrolimus Dosage in the Early Period after Heart Transplantation: A Population Pharmacokinetic Approach

Han, Yong; Zhou, Hong; Cai, Jie; Huang, Jun; Zhang, Jing; Shi, Shaojun; Liu, Yani

doi:10.2217/pgs-2018-0116

Cited by 25 publications

(42 citation statements)

References 57 publications

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“…To date, there has been a plethora of literature focused on tacrolimus dose optimization in solid organ transplant (e.g., kidney, liver, and heart). [22][23][24][25][26] However, solid organ transplant aims to prevent organ rejection, whereas HCT aims to mitigate aGVHD and develop complete tolerance so that graft versus leukemia can be maintained. 27,28 Additionally, baseline organ function differences between patients receiving solid organ transplant and allogeneic HCT also exist.…”

Section: How Might This Change Clinical Pharmacology or Translational Science?mentioning

confidence: 99%

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

Zhu

Campagne

Torrice

et al. 2021

Clinical Translational Sci

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Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model‐predicted tacrolimus steady‐state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady‐state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model‐based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5–10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model‐based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT‐specific covariates to be considered for future prospective studies. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus is a cornerstone immunosuppressant used in patients who undergo organ transplantations. However, because of its narrow therapeutic index and wide interpatient pharmacokinetic (PK) variability, optimizing its dose is crucial to maximize efficacy and minimize tacrolimus‐induced toxicities. Prior to this study, no tacrolimus population PK models have been developed for adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Therefore, research effort was warranted to develop a population PK model that begins to propose more precision tacrolimus dosing and begins to address both a clinical and scientific gap in this patient population. WHAT QUESTION DID THIS STUDY ADDRESS? The study addressed whether there is value in utilizing the observed tacrolimus steady‐state trough concentrations from patients receiving allogeneic HCT within the context of a pre‐existing population PK model developed for kidney transplant. The study also addressed whether there are clinically relevant covariates specific to adult patients receiving allogeneic HCT. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Inclusion of a single steady‐state tacrolimus trough concentration is beneficial to model predictions. The dosing simulation strategy based o...

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Section: How Might This Change Clinical Pharmacology or Translational Science?mentioning

confidence: 99%

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

Zhu

Campagne

Torrice

et al. 2021

Clinical Translational Sci

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“…In addition, it has been used as the first-line drug for patients with liver and renal transplant (16,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Furthermore, it has been demonstrated that tacrolimus may be used to improve the outcome of patients who undergo bone marrow (35)(36)(37)(38)(39)(40)(41)(42), lung (43) and heart transplantation (44). In previous years, clinical experiments have also indicated that tacrolimus has useful applications in systemic-onset juvenile idiopathic arthritis (45)(46)(47)(48), nephrotic syndrome (49)(50)(51)(52)(53)(54)(55), SLE (56)(57)(58)(59)(60)(61)(62)(63)(64)(65), myasthenia gravis (66,67), ul...…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been used as the first-line drug for patients with liver and renal transplant (16,22-34). Furthermore, it has been demonstrated that tacrolimus may be used to improve the outcome of patients who undergo bone marrow ( 35-42 ), lung ( 43 ) and heart transplantation ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

Chen

Wang

et al. 2020

Exp Ther Med

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The present study aimed to establish a population pharmacokinetics model of tacrolimus and further optimize the initial dosing regimen of tacrolimus in pediatric and adolescent patients with lupus nephritis (LN). Pediatric and adolescent patients with LN were recruited between August 2014 and September 2019 at the Children's Hospital of Fudan University (Shanghai, China). Relevant information was used to set up a population pharmacokinetics model with a Nonlinear Mixed Effect Model and the initial dosage regimen was simulated with the Monte Carlo method. Body weight and co-administration of wuzhi capsule were indicated to influence tacrolimus clearance in pediatric and adolescent patients with LN, and at the same body weight, the rate of tacrolimus clearance in patients without vs. with co-administration of wuzhi capsule was 1:0.71. In addition, in patients who were not administered wuzhi capsule, an initial dosage regimen of 0.15 mg/kg/day was recommended for a body weight of 10-23 kg and 0.10 mg/kg/day for 23-60 kg; in patients who were administered wuzhi capsule, an initial dosage regimen of 0.10 mg/kg/day was recommended for a body weight of 10-23 kg and 0.05 mg/kg/day for 23-60 kg. To the best of our knowledge, the present study was the first to establish a population pharmacokinetics model of tacrolimus in order to determine the optimal initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN.

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“…Tacrolimus mainly inhibits the release of interleukin-2, comprehensively inhibits the effect of T lymphocytes and is 100 times stronger than cyclosporine. 1,2 In recent years, tacrolimus has been a first-line drug for liver and kidney transplantation, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] and clinical experiments have shown that its use in heart, 17 lung 18 and bone marrow transplantation [19][20][21][22][23][24][25][26] also has good effects.…”

Section: What Is K Nown and Objec Tive Smentioning

confidence: 99%

Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on theCYP3A5polymorphism and coadministration with Wuzhi capsule

Chen

Wang

et al. 2019

J Clin Pharm Ther

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What is known and objectives Tacrolimus, an immunosuppressant, has been used to treat paediatric systemic lupus erythematosus, but the optimal initial regimen is not clear. The purpose of this study was to explore the optimal initial dose of tacrolimus for children with systemic lupus erythematosus using population pharmacokinetics and pharmacogenomics. Methods Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non‐linear mixed‐effects modelling (NONMEM) analysis. Results and discussion The results showed that weight, the CYP3A5 genotype and combined treatment with Wuzhi capsule can affect tacrolimus clearance in children with systemic lupus erythematosus. Furthermore, at the same weight, the ratios of tacrolimus clearance were 1:2.49:0.57:1.4193 from people who were CYP3A5*3/*3 and did not take Wuzhi capsule, people who had the CYP3A5*1 allele and did not take Wuzhi capsule, people who were CYP3A5*3/*3 and took Wuzhi capsule, and people who had the CYP3A5*1 allele and took Wuzhi capsule, respectively. In addition, we found that 0.10 mg/kg split into two doses was suitable for people with weights from 10 to 60 kg who were CYP3A5*3/*3 and did not take Wuzhi capsule, who were CYP3A5*3/*3 and took Wuzhi capsule, and who had the CYP3A5*1 allele and took Wuzhi capsule. In people who had the CYP3A5*1 allele and did not take Wuzhi capsule, 0.15 mg/kg split into two doses was appropriate for those with weights from 10 to 40 kg and 0.10 mg/kg split into two doses was appropriate for those with weights from 40 to 60 kg. What is new and conclusion This study is the first study to recommend an optimal initial regimen of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration of Wuzhi capsule.

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Prediction of Tacrolimus Dosage in the Early Period after Heart Transplantation: A Population Pharmacokinetic Approach

Cited by 25 publications

References 57 publications

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real‑world data

Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on theCYP3A5polymorphism and coadministration with Wuzhi capsule

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