Population pharmacokinetics and dosing regimen optimization of tacrolimus in Chinese lung transplant recipients

Cai, Xueting; Song, Huizhu; Jiao, Zheng; Yang, Hang; Zhu, Min; Wang, Chengyu; Dong, Wei; Shi, Lingzhi; Wu, Bo; Chen, Jingyu

doi:10.1016/j.ejps.2020.105448

Cited by 29 publications

(65 citation statements)

References 37 publications

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“…In LTx, similar results have been reported in Caucasians [12][13][14]. But studies in Chinese population are limited till now [15,16], and Chinese has a different mutation rates of CYP3A5*3 from Caucasians [6], so, there is a major void in this research area.…”

Section: Introductionsupporting

confidence: 59%

The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

Wang

Zhang

et al. 2021

Preprint

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Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Objective We aim to investigate the effect of cytochrome P450 3A5 (CYP3A5) (rs776746) genotypes on early post-operative Tac metabolism and clinical outcomes in LTx recipients. Methods 90 recipients who underwent LTx from 2017 to 2019 at our institution were enrolled in the study. The effect of CYP3A5 genotype on Tac concentration, dose, dose adjusted concentration (C/D) and interaction with azole antifungals were assessed during week 1–4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. Results CYP3A5*1 carriers had lower C/D than CYP3A5*3/*3 group at all time points (p < 0.05). To reach comparable blood concentrations, CYP3A5*1 carriers required higher doses compared with CYP3A5*3/*3 group (p < 0.05). Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration at week 1, not CYP3A5 genotype, was associated with the incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay (48 (37–68) vs 46(32–57) days, p = 0.264). Kaplan–Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it has no influence on the incidence of AKI, length of hospital stay and mortality.

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Section: Introductionsupporting

confidence: 59%

The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

Wang

Zhang

et al. 2021

Preprint

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“…Although the two CNIs suppress the immune system through similar mechanisms, differences in their side effects can be observed. Studies believe that an important reason for the improvement of renal function parameters in tacrolimus immunosuppressed patients may be that the serum concentration of tacrolimus is reduced by 100 times [ 29 ]. Therefore, the CNI reduction program plays an important role in improving renal function after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Effect of MMF Immunosuppression Based on CNI Reduction on CNI-Related Renal Damage after Lung Transplantation

Tang

Wang

Xue

et al. 2022

Journal of Healthcare Engineering

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In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. The clinical data of age and gender of the two groups were collected, To observe and compare the occurrence of CNI-related renal damage in lung transplant recipients and different immunosuppressants. The CNI dosage of tacrolimus group and cyclosporine A group was compared before and after MMF. The changes of serum creatinine level and serum creatinine clearance rate were measured before MMF administration and 30, 60, and 90 days after MMF administration, to observe the complications of CNI-related renal damage after lung transplantation. Experimental results showed that there were 16 cases (14.55%) of CNI-related renal damage in lung transplant recipients and different immunosuppressants, including 10 cases (11.36%) in males, 6 cases (27.27%) in females, 11 cases (12.09%) in tacrolimus group, and 5 cases (26.32%) in cyclosporine A group. There was no significant difference between the two groups ( P > 0.05 ). Compared with MMF before and after administration, CNI dosage of cyclosporine A group and tacrolimus group decreased significantly ( P < 0.01 ). Compared with MMF before administration, serum creatinine level decreased and serum creatinine clearance rate increased significantly ( P < 0.05 ). In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.

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“… 8 , 51 , 52 This phenomenon can be explained by the poor water solubility of tacrolimus and its low transmembrane permeability in the intestine, which may result in its low and variable oral bioavailability and limited absorption rate in the gastrointestinal tract. 2 The non-linear kinetics of tacrolimus warrant further investigation with a larger sample size.…”

Section: Discussionmentioning

confidence: 99%

“…The bioavailability of tacrolimus is low and highly variable (range 4–89%) owing to its poor solubility and extensive first-pass effect. 2 Therapeutic drug monitoring (TDM) is implemented to individualize the dosage of tacrolimus based on the trough concentration (C 0 ) and to reduce the risks of toxicity and rejection risk. 3 In general, pharmacokinetic parameters reach a steady state approximately 3 d following therapy initiation.…”

Section: Introductionmentioning

confidence: 99%

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

Chen¹,

Yang²,

Wang³

et al. 2021

PGPM

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Purpose In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients. Patients and Methods We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated. Results The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h −1 , and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect. Conclusion Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.

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Population pharmacokinetics and dosing regimen optimization of tacrolimus in Chinese lung transplant recipients

Cited by 29 publications

References 37 publications

The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

The Impact of Cytochrome P450 3A5 Genotype on Early Tacrolimus Metabolism and Clinical Outcomes in Lung Transplant Recipients

Effect of MMF Immunosuppression Based on CNI Reduction on CNI-Related Renal Damage after Lung Transplantation

Wuzhi Capsule Dosage Affects Tacrolimus Elimination in Adult Kidney Transplant Recipients, as Determined by a Population Pharmacokinetics Analysis

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