Chinese Liver Transplant Recipients Research Articles

Impact of genetic polymorphisms on tacrolimus trough blood concentration in Chinese liver transplant recipients.

Purpose: The aim of this study was to analyze the effects of various genetic polymorphisms and clinical factors on tacrolimus (TAC) concentration in the convalescence period (CP) and stabilization period (SP) post-liver transplantation. Patients & methods: A total of 13 SNPs were genotyped in 97 Chinese liver transplant recipients. Associations between SNPs and TAC trough blood concentration/dose ratio (C0/D) were analyzed using different genetic models in both CP and SP. Results: Only five SNPs were significantly associated with TAC log (C0/D) in the CP, and none showed a significant association in the SP. We identified rs15524 (CYP3A5), rs9200 (C6), albumin and creatinine as independent predictors of TAC C0/D in the CP. Furthermore, a final model in the CP explained a total of 30.5% TAC variation. Conclusion: Our study results suggest that in the early stages post-transplantation surgery, recipients' genetic and clinical factors exert a short-term impact on TAC metabolism that gradually decreases with time.

Individual dose recommendations for drug interaction between tacrolimus and voriconazole in adult liver transplant recipients: A semiphysiologically based population pharmacokinetic modeling approach

The magnitude of drug-drug interaction between tacrolimus and voriconazole is highly variable, and individually tailoring the tacrolimus dose when concomitantly administered with voriconazole remains difficult. This study aimed to develop a semiphysiologically based population pharmacokinetic (semi-PBPK) model and a web-based dashboard to identify the dynamic inhibition of tacrolimus metabolism caused by voriconazole and provide individual tacrolimus regimens for Chinese adult liver transplant recipients. A total of 264 tacrolimus concentrations and 146 voriconazole concentrations were prospectively collected from 32 transplant recipients. A semi-PBPK model with physiological compartments including the gut wall, portal vein, and liver was developed using the nonlinear mixed-effects modeling software NONMEM (version 7.4). A web-based dashboard was established in R software (version 3.6.1) to recommend the individual tacrolimus regimens when concomitantly administered with voriconazole. The reversible inhibition of tacrolimus metabolism caused by voriconazole was investigated in both the liver and the gut wall. Moreover, voriconazole could highly inhibit the CYP3A activity in the gut wall more than in the liver. BMI and postoperative days were identified as significant covariates on intrinsic intestinal and hepatic clearance of tacrolimus, respectively. Age and postoperative days were identified as significant covariates on the volume of distribution of voriconazole. The individual tacrolimus regimens when concomitantly administered with voriconazole could be recommended in the dashboard (https://tac-vor-ddi.shinyapps.io/shinyapp3/). In conclusion, the semi-PBPK model successfully described the dynamic inhibition process between tacrolimus and voriconazole, and the web-based dashboard could provide individual tacrolimus regimens when concomitantly administered with voriconazole.

Donor and recipient polymorphisms of MAPK signaling pathway genes influence post-transplant liver function in Chinese liver transplant patients taking tacrolimus

Tacrolimus (TAC) is an immunosuppressive drug that is widely used for patients who underwent liver transplantation. In addition to inhibiting the action of calcineurin, TAC also exerts its immunosuppressive effects by interfering with mitogen activated protein kinase (MAPK) pathway. In this study, we investigated the impact of both recipient and donor genetic polymorphisms of MAPK kinase kinase (MAP3K) genes on clinical events in Han Chinese liver transplantation recipients taking TAC. Fifty-seven tag SNPs of 11 genes (MEKK1, MEKK2, MEKK4, MLK1, MLK3, ASK1, TAO1, TAO2, Tpl2, TAK1 and ZAK1) in the MAPK pathway were detected by MALDI-TOF MS assay in 175 TAC-treated liver transplant recipients. The associations of SNPs with incidence of acute rejection, TAC-induced acute nephrotoxicity, and post-transplantation liver and kidney function were explored using Kaplan-Meier survival analysis, Cox-proportional hazard model and linear mixed model, respectively. For the sites significantly associated with clinical events, the dual-luciferase reporter gene system was used to perform preliminary function verification. The results showed that (1) Donor-recipient combinational (D-R) MEKK1 rs62355944 and D-R MLK1 rs8006424 genotypes were significant influence factors of post-transplantation γ-glutamyl transpeptidase (GGT) level (P < 0.0001); (2) D-R MLK1 rs8006424 genotypes were found to significantly affect the alkaline phosphatase (ALP) level after transplantation (P < 0.0001). The results of the dual luciferase reporter gene system demonstrated that the luciferase activity of the pGL3-rs8006424A was significantly higher than that of pGL3-rs8006424G (3.47 ± 0.10 vs 2.97 ± 0.08, P = 0.002). Therefore, MEKK1 rs62355944 and MLK1 rs8006424 might serve as biomarkers to predict post-transplant liver function in liver transplant patients.

Population Pharmacokinetic Modeling Combined With Machine Learning Approach Improved Tacrolimus Trough Concentration Prediction in Chinese Adult Liver Transplant Recipients.

This study aimed to develop and evaluate a population pharmacokinetic (PPK) combined machine learning approach to predict tacrolimus trough concentrations for Chinese adult liver transplant recipients in the early posttransplant period. Tacrolimus trough concentrations were retrospectively collected from routine monitoring records of liver transplant recipients and divided into the training data set (1287 concentrations in 145 recipients) and the test data set (296 concentrations in 36 recipients). A PPK model was first established using NONMEM. Then a machine learning model of Xgboost was adapted to fit the estimated individual pharmacokinetic parameters obtained from the PPK model with Bayesian forecasting. The performance of the final PPK model and Xgboost model was compared in the test data set. In the final PPK model, tacrolimus daily dose, postoperative days, hematocrit, aspartate aminotransferase, and concomitant voriconazole, were identified to significantly influence the clearance. The postoperative days along with hematocrit significantly influence the volume of distribution. In the Xgboost model, the first 5 predictors for predicting the clearance were concomitant with voriconazole, sex, single nucleotide polymorphisms of CYP3A4*1G and CYP3A5*3 in recipients, and tacrolimus daily dose, for the volume of distribution were postoperative days, age, weight, total bilirubin and graft:recipient weight ratio. In the test data set, the Xgboost model showed the minimum median prediction error of tacrolimus concentrations, less than the PPK model with or without Bayesian forecasting. In conclusion, a PPK combined machine learning approach could improve the prediction of tacrolimus concentrations for Chinese adult liver transplant recipients in the early posttransplant period.

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil.

The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-β-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates for the in vivo BE test. Furthermore, a physiologically based predictive in vitro dissolution test under both fasting and fed conditions would be a new trend for the BE studies of all other HV drug products.

Population pharmacokinetics of sirolimus in Chinese adult liver transplant recipients: a retrospective study

Considering the significant interindividual variability and a narrow therapeutic index, we aimed to determine the population pharmacokinetics (PPK) of sirolimus and identify the factors in Chinese adult liver transplant recipients. Data were retrospectively extracted from adult liver transplant recipients receiving sirolimus in our hospital. The trough blood concentration data, obtained from traditional therapeutic drug monitoring-based dose adjustments, were used to develop a population pharmacokinetic model by non-linear mixed-effects modelling (NONMEM). The effect of demographic features, biological characteristics and concomitant medications was measured. The final model was verified by visual prediction check (VPC), bootstrap, and simulation. One hundred and sixteen blood concentrations from 63 patients were analysed. The PPK of sirolimus could be described by a one-compartment model with first-order absorption. Covariate analysis indicated that voriconazole co-therapy significantly decreased the oral clearance (CL) of sirolimus. The results of VPC and Bootstrap demonstrated that the final pharmacokinetic model adequately predicted observed concentrations. The simulation results showed that the dosage regimen of sirolimus should be reduced to 0.25 ∼ 0.45 mg/day for adult liver transplant recipients co-administered with voriconazole. The present study developed and validated a sirolimus PPK model for Chinese adult liver transplant recipients, and voriconazole co-therapy was found to be a significant covariate in the model. These results provide important information for clinicians to optimise the treatment regimens of sirolimus in Chinese adult liver transplant recipients.

Effects of Postoperative Day and NR1I2 on Tacrolimus Clearance in Chinese Liver Transplant Recipients-A Population Model Approach.

We aimed to explore the new biomarkers influencing tacrolimus in vivo behavior in Chinese liver transplant recipients. A total of 418 drug concentration samples of 41 liver transplant patients were collected for modeling. A population pharmacokinetic model was developed using the nonlinear mixed-effects modeling approach. The potential covariates, such as postoperative day (POD), age, body weight, hepatic and renal function, and recipient genetic polymorphisms (ABCB1, CYP3A4, CYP3A5, NR1I2) were evaluated using forward-inclusion and backward-elimination methods. A 1-compartment model was used describing the in vivo behavior of tacrolimus in liver transplant patients. The estimates of CL/F and V/F were 8.88 L/h and 495.82 L, respectively. Two covariates, POD and NR1I2 rs2276707 genotypes, were incorporated into the final population pharmacokinetic model, and they could significantly impact the CL/F: CL/F (L/h) = 8.88 × (POD/16)0.18 × e0.91 × NR1I2 × eηCL . The model evaluation and validation indicated a stable and precise performance of the final model. The functional annotation using ENCODE data indicated that rs2276707 was located on the higher peak of the H3K4Me1 and H3K4Me3 histone marker. To our knowledge, this is the first report indicating NR1I2 rs2276707 genotypes is another biomarker impacting tacrolimus clearance in liver transplant recipients. The NR1I2 gene polymorphism may affect the in vivo behavior of tacrolimus by regulating gene expression.

Expert consensus on management of metabolic disease in Chinese liver transplant recipients.

Metabolic disease, including diabetes mellitus, hypertension, dyslipidemia, obesity, and hyperuricemia, is a common complication after liver transplantation and a risk factor for cardiovascular disease and death. The development of metabolic disease is closely related to the side effects of immunosuppressants. Therefore, optimization of the immunosuppressive regimen is very important for the prevention and treatment of metabolic disease. The Chinese Society of Organ Transplantation has developed an expert consensus on the management of metabolic diseases in Chinese liver transplant recipients based on recent studies. Emphasis is placed on the risk factors of metabolic diseases, the effect of immunosuppressants on metabolic disease, and the prevention and treatment of metabolic diseases.

Impact of Donor and Recipient CYP3A5*3 Genotype on Tacrolimus Population Pharmacokinetics in Chinese Adult Liver Transplant Recipients.

Background: Tacrolimus (TAC) is widely used after liver transplantation, but the therapeutic window is narrow. Objective: The purpose was to study both donor and recipient CYP3A5*3 genotypes affecting TAC apparent clearance rate (CL/F) and investigate a TAC population pharmacokinetic (PPK) model in Chinese liver transplant recipients for potential starting-dose individualized medication. Methods: A data set of 721 TAC concentrations was obtained from 43 adult liver transplant recipients. The TAC PPK model was analyzed using nonlinear mixed-effects modeling. Potential covariates, including demographic characteristics, physiological and pathological data, concomitant medications, and CYP3A5*3 genotype, were evaluated. The final model was validated using normalized prediction distribution errors and bootstrapping. Results: A 2-compartment model with first-order absorption and elimination was used to describe TAC disposition. Population estimates of TAC, CL/F, apparent central distribution volume (V2/F), rate of absorption (Ka), and apparent peripheral distribution volume (V3/F) were 18.1 L/h (12%), 72.7 L (34%), 0.163 h-1 (17%), and 412 L (21%), respectively. The model and estimated parameters were found to be stable. Other covariates did not influence TAC CL/F. Both donor and recipient CYP3A5*1 genotypes were significantly correlated with TAC clearance, and CL/F was 1.70-fold higher in both donor and recipient CYP3A5*1 carriers than in noncarriers among Chinese liver transplant recipients. Conclusion and Relevance: A PPK model of TAC was established in Chinese adult liver transplantation recipients for starting-dose individualized medication, which can be expanded to optimize clinical efficacy and minimize toxicity with therapeutic drug monitoring.

Retraction: Association of MDR1 Gene SNPs and Haplotypes with the Tacrolimus Dose Requirements in Han Chinese Liver Transplant Recipients.

Retraction: Association of MDR1 Gene SNPs and Haplotypes with the Tacrolimus Dose Requirements in Han Chinese Liver Transplant Recipients.

Prospective Study on Sexual Dysfunction in Male Chinese Liver Transplant Recipients.

In patients with end-stage liver disease, hypogonadism and erectile dysfunction are often seen. This study was to determine the incidence of erectile dysfunction before and after liver transplantation (LT) with correlation to change in sex hormone levels from a Chinese cohort. This prospective longitudinal study was registered with The University of Hong Kong Clinical Trials Centre (HKUCTR-1563). The Institutional Review Board approval number is UW-12-273. The study period was from January 2012 to December 2016. Adult male patients with end-stage liver disease enlisted for LT were recruited on informed written consent. All recruited patients were to complete a cross-sectional cohort questionnaire—International Index of Erectile Function, version 5 (IIEF5)—and to receive serum sex hormone checks before and after LT. Twenty-eight patients who underwent LT were included in the analysis. The included patients had significantly reduced prolactin (p < .001) and 17-beta-estradiol (p = .024) after LT. There was also a significant drop of IIEF5 score at 1 month after LT, but the score returned to pre-LT level at 6 months. This study demonstrated that there was improvement in sex hormone levels after LT, namely, normalization of estradiol level and lowering of prolactin and progesterone levels. However, improvement in sex hormone levels did not translate into improvement of erectile dysfunction.

Prospective Trial on Sexual Dysfunction in Male Chinese Liver Transplant Recipients

Prospective Trial on Sexual Dysfunction in Male Chinese Liver Transplant Recipients

Association of CYP3A5, CYP2C8, and ABCB1 Polymorphisms With Early Renal Injury in Chinese Liver Transplant Recipients Receiving Tacrolimus

BackgroundThe purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus. MethodsCYP3A5, ABCB1, and CYP2C8 polymorphisms were genotyped in the Chinese liver transplant recipients in the study receiving tacrolimus for at least 2 years by polymerase chain reaction and high-resolution melting method. Serum cystatin C and urine microprotein (α1-microglobulin, microalbumin, transferrin, and immunoglobulin) of liver transplant recipients were used to determine both the status of early renal injury and the lesion part. ResultsWe documented 3 genotypes of CYP3A5 and ABCB1 and only 2 genotypes of CYP2C8 in our cohort. The levels of cystatin C and all 4 indicators of the urine microprotein in the recipient group were significantly higher than those in the control group (P < .05). The concentrations of transferrin differed significantly in each CYP3A5 genotype group (P < .05). Based on diverse CYP2C8 genotypes, we divided all the recipients into 2 groups: CYP2C8*1*1 group and CYP2C8*3*1 group. The concentrations of α1-microglobulin and cystatin C differed significantly between the 2 groups (P < .05). For CYP2C8*3, the positive predictive value is 68.5% and negative predictive value is 70.2%. For CYP3A5*3, the positive predictive value is 55.3% and negative predictive value is 60.4%. ConclusionsCYP2C8*3 and CYP3A5*3 appear to be predictive of risk of tacrolimus-induced early renal impairment. CYP3A5*3 was associated with the risk of early renal glomerular lesion, while CYP2C8*3 was associated with the risk of the tubulointerstitial injury. ABCB1 polymorphisms (both C3435T and C1236T) were not associated with the early renal injury in liver transplant recipients.

A new donors’ CYP3A5 and recipients’ CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients

AimThe purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors.MethodsIn this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included.ResultsBoth donors’ CYP3A5*3 and recipients’ CYP3A4*1G had a correlation with Tac pharmacokinetics at four weeks (all P<0.05), except recipients’ CYP3A4*1G nearly had an association at week 2 (P=0.055). The model of donors’ CYP3A5*3, recipients’ CYP3A4*1G, and total bilirubin (TBL), for the prediction of Tac disposition, was better than donors’ CYP3A5*3 only at week 1, 2, and 3 (P=0.010, P=0.007, and P=0.010, respectively), but not apparent at week 4 (P=0.297). Besides, when the P value was greater than or equal to 0.6685 after considering the false-positive rate R=10%, the patients were considered to have a faster metabolism, according to the mentioned model. Interestingly, we found that if more than or equal to two alleles A were present in the combination of donors’ CYP3A5*3 and recipients’ CYP3A4*1G genotype, there was a lower Tac C/D ration at week 1, 2, and 3 (P<0.001, P=0.001, and P<0.001), except at week 4 (P=0.082), and the probability of new-onset hypertension was lesser (P<0.001).ConclusionsThese data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention, early diagnosis of new-onset hypertension in Chinese LT recipients.

The application of the necessity-concerns framework in investigating adherence and beliefs about immunosuppressive medication among Chinese liver transplant recipients

Abstract Objective This study aimed to explore adherence to and beliefs about immunosuppressive medication using the Necessity-Concerns Framework (NCF) in liver transplant recipients. Methods A cross-sectional study performed in recipients who were at least 3 months post liver transplantation. A convenience sample of 243 recipients was recruited. Self-reported medication adherence was measured by the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS). The NCF was operationalized using the Beliefs about Medication Questionnaire (BMQ) to assess the beliefs about necessity and concerns with taking immunosuppressive medication. Results One-hundred-forty-five liver transplant recipients were non-adherent (59.67%). Compared to adherers, non-adherers had lower beliefs regarding the necessity of taking immunosuppressive medication and lower scores on the necessity-concerns different from adherers. Conclusions Non-adherence is common in liver transplant recipients. Non-adherers hold beliefs that are different from adherers. Efforts to increase adherence should be made by targeting medication beliefs.

The application of the necessity-concerns framework in investigating adherence and beliefs about immunosuppressive medication among Chinese liver transplant recipients

The application of the necessity-concerns framework in investigating adherence and beliefs about immunosuppressive medication among Chinese liver transplant recipients

Cytokine Profile in Calcineurin Inhibitor-Induced Chronic Nephrotoxicity in Chinese Liver Transplant Recipients.

Calcineurin inhibitor-associated chronic nephrotoxicity threatens the prognosis of liver transplant recipients. This study aimed to study the mechanisms involved by identifying the cytokine profiles in tacrolimus (Tac)-induced nephrotoxicity. We enrolled 125 living-donor liver transplant recipients. All of the recipients had normal serum cystatin (Cys) C and urine microalbumin before transplantation. Theyreceived a Tac-based immunosuppressive regimen (Tac+ mycophenolate mofetil+ prednisone) thereafter. Patients were grouped according to Cys-C results (measured a mean 3.55 ± 1.89 years after transplantation) as a measure of renal injury: the early renal damage group was Cys-C >1 mg/L, and normal renal function was Cys-C≤1 mg/L. Serum levels of 10 cytokines and chemokines, as well as urine proteins including α1 microglobulin, microalbumin, transferrin, and immunoglobulin G, were compared between groups. In the early renal damage group, the concentration of interferon-γ-induced protein (IP) 10 was higher and monocyte chemotactic protein (MCP) 1 was lower compared with the group with normal renal function (P= .027 and .048, respectively). Multivariate logarithmic regression analysis showed that IP-10 and MCP-1 were independently correlated with renal damage. High level of IP-10 and low level of MCP-1 may be involved in renal injury and therefore may indicate poor prognosis. IP-10 could be a target for renal injury treatment after liver transplantation. Further studies with larger sample sizes are recommended to validate the study results.

Dose regimens for Chinese adult liver transplant recipients according to the genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A5 in recipients and donors.

Genetic polymorphisms of the P450 2C9 enzyme (CYP2C9), CYP2C19 and CYP3A5 gene are known to affect the metabolism of many drugs applied in liver transplant recipients, such as warfarin, voriconazole, and tacrolimus. The aim of this study was to recommend dose regimens for the liver recipients based on CYP2C9, CYP2C19, and CYP3A5 genotypic combinations of liver transplant recipients and their donors. 91 adult Han Chinese liver transplant recipients who underwent orthotopic liver transplantation at Tianjin First Central Hospital, China, between 2013 and 2014 were included in this study. CYP2C9*2, CYP2C9*3, CYP2C19* 2, CYP2C19*3 and CYP3A5*3, in both liver recipients and their grafted liver were tested by polymerase chain reaction-restriction fragment length polymorphism. The dose regimens for the liver recipients were recommended based on CYP genotypic combinations of the recipients and their donors. In the liver transplant recipients, the frequencies of CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP3A5*3 were found to be 2.75%, 4.40%, 0%, 24.18%, and 75.27%, respectively. Allele frequencies were significantly different for CYP2C9*2, CYP2C19*2, and CYP2C19* 3 (p < 0.001) when comparing the recipients with Chinese, Eastern Asians and Caucasians populations. Most dose regimens of drugs, especially of immunosuppressive drugs, should be adjusted according to the variant metabolism activity affected by the genetic polymorphisms in both recipients and their grafted liver. The dose regimens would present considerable intraand inter-patient variability in liver transplant recipients since the genetic polymorphisms of P450 enzyme in their grafted liver might complicate the metabolism of drugs in liver transplant recipients. Giving careful consideration to the CYP genotypic combinations of transplant recipients and donors in clinical dose regimens could optimize outcomes.

Effects of CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients

1. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene-encoding P-glycoprotein (ABCB1), on the PK parameters in Chinese adult liver transplant recipients.2. Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs.3. A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6 L/h and 225 L, respectively. The absorption rate constant (Ka) was fixed at 4.48 h−1. The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F.4. Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.

A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients.

To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication. A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, p.o.) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check. A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus. Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.