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Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation.

ABSTRACT: Background:In order to improve the precision of treatment with tacrolimus in Chinese patients undergoing pediatric liver transplantation, the optimum initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics. Methods:Demographic data, clinical parameters, drug combinations and pharmacogenomics were integrated to build a population pharmacokinetic model using NONMEM. Additionally, Monte Carlo simulations were used to optimize the recommended initial dose. Results:Weight, patient cytochrome 450 3A (CYP3A)5 genotype, and co-administration with wuzhi-capsule (WZ) were incorporated into the final model. For children with a CYP3A5*3/*3 genotype not co-administered WZ, 0.10 mg/kg/day split into two doses was recommended for patients weighing 5-17 kg, and 0.05 mg/kg/day split into two doses was recommended for patients weighing 17-60 kg. For children with a CYP3A5*1 allele not co-administered WZ, 0.25 mg/kg/day for patients weighing 5-10 kg, 0.20 mg/kg/day for patients weighing 10-17 kg, 0.15 mg/kg/day for patients weighing 17-36 kg, and 0.10 mg/kg/day for patients weighing 36-60 kg; all split into two doses was recommended. For children with a CYP3A5*3/*3 genotype co-administered WZ, 0.10 mg/kg/day for patients weighing 5-11 kg, and 0.05 mg/kg/day for patients weighing 11-60 kg; both split into two doses was recommended. For children with a CYP3A5*1 allele who were co-administered WZ, 0.20 mg/kg/day for patients weighing 5-10 kg, 0.15 mg/kg/day for patients weighing 10-22 kg, and 0.10 mg/kg/day for patients weighing 22-60 kg all split into two doses was recommended. Conclusions:The optimal initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics in Chinese patients undergoing pediatric liver transplantation.

SUBMITTER: Chen X

PROVIDER: S-EPMC7658763 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation.

Chen Xiao X Wang Dong-Dong DD Xu Hong H Li Zhi-Ping ZP

Translational pediatrics 20201001 5

<h4>Background</h4>In order to improve the precision of treatment with tacrolimus in Chinese patients undergoing pediatric liver transplantation, the optimum initial dose of tacrolimus was determined based on population pharmacokinetics and pharmacogenomics.<h4>Methods</h4>Demographic data, clinical parameters, drug combinations and pharmacogenomics were integrated to build a population pharmacokinetic model using NONMEM. Additionally, Monte Carlo simulations were used to optimize the recommende ...[more]

PMID: 33209719

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Project description:Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

Dataset Information

Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation.

Publications

Population pharmacokinetics and pharmacogenomics of tacrolimus in Chinese children receiving a liver transplant: initial dose recommendation.

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