The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients

Prytuła, Agnieszka; Cransberg, Karlien; Bouts, Antonia H.; Schaik, Ron H.N. van; Jong, Huib de; Wildt, Saskia N. de; Mathôt, Ron A. A.

doi:10.1007/s40262-016-0390-7

Cited by 32 publications

(45 citation statements)

References 67 publications

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“…Tacrolimus is strongly bound to red blood cells . Several studies showed that plasma tacrolimus concentrations change with altering hematocrit levels . However, Storset et al suggested that this influence might not always be clinically relevant because hematocrit is not expected to influence the unbound, therapeutically active fraction of tacrolimus .…”

Section: Discussionmentioning

confidence: 99%

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

Defrancq

Wilde

Raes

et al. 2019

Pediatric Transplantation

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Background This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. Methods This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1‐5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. Results We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy‐proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor‐specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0‐1.1; P = 0.03) and 1.04 (95% CI 1.0‐1.1; P = 0.05), respectively. Conclusions Our results highlight the impact of biological factors on TAC IPV during the early LT follow‐up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

Defrancq

Wilde

Raes

et al. 2019

Pediatric Transplantation

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“… AUC area under the concentration time curve, wb whole blood a Targets according to our local hospital protocol which is based on the following references: [3, 8]…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the intra- and inter-individual pharmacokinetic variability is high [1, 5]. Previously, body weight [6–8], CYP3A5 polymorphisms [6–9], age [9, 10] and hematocrit level [6, 7] were found to have significant effects on pharmacokinetic variability in pediatric kidney transplant patients, especially in the early phase after transplantation. Due to the large pharmacokinetic variability, individualizing tacrolimus dosing regimens by performing therapeutic drug monitoring (TDM) to optimize the therapeutic effect and minimize adverse effects is essential and currently the standard of care.…”

Section: Introductionmentioning

confidence: 99%

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients

et al. 2018

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BackgroundTacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients.MethodsData were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated.ResultsIn total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations.ConclusionA critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.Electronic supplementary materialThe online version of this article (10.1007/s00467-018-4117-x) contains supplementary material, which is available to authorized users.

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“…Many studies demonstrated a non‐linear relationship between drug clearance and body weight in paediatric patients . As is well known, tacrolimus is metabolized by CYP3A5 , and its clearance rate is different in different genotypes . Wuzhi capsule is a Chinese patent medicine whose primary active constituents are schisandrin, schisantherin A, and schisandrol B, and it can increase tacrolimus concentration via inhibiting tacrolimus metabolism enzyme, CYP3A .…”

Section: Discussionmentioning

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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The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients

Abstract: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A51 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A51 allele have higher weight-normalised tacrolimus dose requirements.

Cited by 32 publications

References 67 publications

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients

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

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The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients

Abstract: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.

Cited by 32 publications

References 67 publications

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

Intra‐patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients

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

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Abstract: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A51 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A51 allele have higher weight-normalised tacrolimus dose requirements.