Tacrolimus Apparent Clearance Research Articles

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4years old after liver transplantation and to develop individualized tacrolimus dosing software. A total of 663 blood concentrations from 85 patients aged 4.57months to 3.97years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Elevation of tacrolimus concentration after administration of methotrexate for treatment of graft-versus-host disease in pediatric patients received allogeneic hematopoietic stem cell transplantation

BackgroundMethotrexate (MTX) is used to treat graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, a case was encountered in which the blood concentration of tacrolimus (TCR) at steady state increased after intravenous MTX administration for GVHD treatment (therapeutic IV-MTX administration). Therefore, this study aimed to investigate the effect of therapeutic IV-MTX administration on the pharmacokinetics of TCR.MethodsThis single-center, retrospective, observational study included patients who underwent allo-HSCT and received therapeutic IV-MTX administration during immunosuppressive therapy with continuous intravenous infusion (CIV) of TCR from April 2004 to December 2021. Here, each therapeutic IV-MTX administration was defined as a case and independently subjected to subsequent analyses. The blood concentration of TCR at steady state (Css), ratio of Css to daily TCR dose (C/D), and clinical laboratory data were compared before and after therapeutic IV-MTX administration. In addition, dose changes in the TCR after therapeutic IV-MTX administration were evaluated.ResultsTen patients (23 cases) were included in this study. The C/D value significantly increased after therapeutic IV-MTX administration (median: 697 vs. 771 (ng/mL)/(mg/kg), 1.16-fold increase, P < 0.05), indicating a reduction in the apparent clearance of TCR. Along with the increase in C/D, significant increases were observed in aspartate transaminase level (median: 51.0 vs. 92.9 U/L, P < 0.01) and alanine aminotransferase level (median: 74.5 vs. 99.4 U/L, P < 0.01) indicating that liver injury after therapeutic IV-MTX administration contributes to the observed C/D increase. In addition, the daily dose of TCR was reduced in 11 cases (47.8%) after therapeutic IV-MTX administration, and the relative frequency of dose reduction tended to be higher than that of dose increase (median: 37.5% vs. 0.0%, P = 0.0519, permuted Brunner-Munzel test). The magnitude of dose reduction was 18.8% (7.4–50.0%) in the 11 cases with dose reduction.ConclusionsTherapeutic IV-MTX administration cause a significant increase in C/D, which requires TCR dose reduction. Careful therapeutic drug monitoring of TCR is needed after therapeutic IV-MTX administration in patients receiving immunosuppressive therapy with TCR after allo-HSCT.

Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry.

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra- and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin-induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate-release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed-effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49ng/mL, 6.5%, and 3.09ng/mL, respectively. Prospective testing of this equation is warranted.

Prediction of tacrolimus dosage in the early period after heart transplantation: a population pharmacokinetic approach.

The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients. A total of 707 tacrolimus concentrations from 107 adult heart transplant patients were included in model development. The effects of demographic, clinical factors and CYP3A5 genotype on tacrolimus clearance were evaluated using a nonlinear mixed-effects modeling. 24 patients with 106 tacrolimus concentrations were used for external validation. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution of tacrolimus were 13.7 l/h and 791 l, respectively. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). A predictive performance was further confirmed in an external validation by Bayesian estimation. Recommended dose regimens were obtained by simulations based on the established model. This is the first population pharmacokinetic study conducted in Chinese heart transplant recipients. These findings are of great importance with regards to tacrolimus dose optimization in heart transplantation patients.

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation.

BackgroundMultiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration.ObjectivesThe objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis.MethodsA total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM®) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines.ResultsThe data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day.ConclusionDuring the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.

PS 08-28 THE EFFECT OF CYP3A4 AND CYP3A5 POLYMORPHISMS ON THE TACROLIMUS PLASMA CONCENTRATION IN CHINESE POST RENAL TRANSPLANT RECIPIENTS

Objective: The purpose of this study was to identify the proportion of CYP3A4 and CYP3A5 gene polymorphisms in Chinese renal transplant recipients, and to study the effect of CYP3A4 and CYP3A5 gene polymorphisms on Concentration/Dose(C0/D) of tacrolimus, and to further develop a population pharmacokinetics model for tacrolimus in Chinese renal transplant recipients. Design and Method: 110 recipients with post renal transplant hypertension were genotyped for CYP3A4*1G and CYP3A5*3 using polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP). 70 recipients received tacrolimus at least 1 week and tacrolimus trough levels(C0) were determined. The population pharmacokinetics model, based on tacrolimus plasma concentrations of 188 renal transplant patients, was established using the nonlinear mixed-effect modeling software. Results: We genotyped 110 recipients for CYP3A4 (47.27% CYP3A4*1/*1; 48.18% CYP3A4*1*1G and 4.55% CYP3A4*1G*1G) and CYP3A5 (5.45% CYP3A5*1/*1; 50.00% CYP3A5*1/*3 and 44.55% CYP3A5*3/*3). Among the 70 recipients with post renal transplant hypertension, patients with CYP3A4*1*1 showed a significantly higher C0/D compared with the CYP3A4*1*1G and CYP3A4*1G*1G group (p < 0.05); While the C0/D of CYP3A5*3*3 group was significantly higher than the CYP3A5*1*1 and CYP3A5*1*3 group (p < 0.05). A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In the final model, clearance (CL/F), distribution volume (Vd/F) and Ka was 30.1L h-1, 3420L and 3.09h-1 respectively. And the CYP3A5*3, hemoglobin and direct bilirubin had significant effect on CL/F, and postoperative days (POD) showed significant influence on Vd/F. Conclusions: Most patients carried the wild allele CYP3A4*1 (G20230A) and the mutant allele CYP3A5*3 (A6986G). The C0/D of tacrolimus was well associated with the CYP3A4*1G and CYP3A5*3 polymorphism. The population pharmacokinetics findings suggest that CYP3A5*3 polymorphisms, hemoglobin and direct bilirubin are determinant factors in the apparent clearance of tacrolimus.

Population pharmacokinetics of tacrolimus in Thai kidney transplant patients: comparison with similar data from other populations.

Tacrolimus, the most widely used calcineurin inhibitor in kidney transplantation, has a narrow therapeutic window with high interindividual variability in its pharmacokinetics. Clinically feasible models that combine important factors may help guide individual tacrolimus dosage adjustment in kidney transplant patients. The purpose of this study was to develop a population pharmacokinetic model and investigate the influence of clinical factors on the pharmacokinetics of tacrolimus in adult Thai kidney transplant patients from routine data monitoring. A total of 1183 whole blood concentrations from 96 patients were characterized using nonlinear mixed-effects modelling. Clinical factors tested for influence on pharmacokinetic parameters were weight, haemoglobin, duration of tacrolimus therapy, prednisolone dose, serum albumin and estimated glomerular filtration rate. A one-compartment model with first-order absorption best described the data. The population estimate of tacrolimus apparent clearance (CL/F) and apparent volume of distribution (V/F) in the final population model was 21·5L/h (95% CI; 18·38, 24·34) and 333L (95% CI; 222·66, 484·35), respectively. CL/F increased with decreasing haemoglobin levels and decreased with increasing duration of tacrolimus therapy (both P<0·001). The population pharmacokinetic equationthat predicted CL/F of tacrolimus was CL/F=21·5×exp((-0·05 () (HB) (-11·8))) ×(DOT/125)(-0·06) , where CL/F was tacrolimus apparent oral clearance (L/h), HB was haemoglobin levels (g/dL), and DOT was duration of tacrolimus therapy (days). No covariates significantly influenced V/F. The first population pharmacokinetic model of tacrolimus in Thai adult kidney transplant patients was developed and validated. Haemoglobin and duration of tacrolimus therapy could partly explain the interindividual variability in the apparent clearance of tacrolimus. This manuscript also provides a summary review of previously reported population pharmacokinetic models of twice daily tacrolimus in adult kidney transplant recipients.

Influence of donor-recipient CYP3A4/5 genotypes, age and fluconazole on tacrolimus pharmacokinetics in pediatric liver transplantation: a population approach.

To characterize the effect of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes as well as relevant patient characteristics on tacrolimus pharmacokinetics in pediatric liver transplantation. Data from 114 pediatric liver transplant recipients were retrospectively collected during the first 3 months following transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling, including characterization of influential covariates. A two-compartment model with first order elimination best fitted the data. Estimates of apparent volume of the central compartment, intestinal clearance, hepatic clearance and intercompartmental clearance were 79 l, 0.01 l/h, 10.9 l/h and 105 l/h, respectively. Time post-transplantation, recipient age, donor CYP3A5 and CYP3A4 genotypes and fluconazole administration significantly influenced tacrolimus apparent clearance while bodyweight influenced volume of distribution. The proposed model displayed acceptable fitting performances and enabled identification of statistically significant and clinically relevant covariates on tacrolimus pharmacokinetics in the early pediatric post liver transplantation period.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients.

To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)(0.75) x EXP(-0.00158 x TPT) x EXP(0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h(-1) kg(-1) (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

The cytochrome P450 (CYP) 3A4*22 allelic status influences the pharmacokinetics of tacrolimus independently of an individual's CYP3A5 genotype. In their recent publication, Passey et al described an algorithm that predicts tacrolimus apparent clearance (CL/F) by taking into account the age and CYP3A5 genotype of a patient, time after kidney transplantation, whether the transplantation was performed at a steroid-sparing center or not and whether the patient was treated with a calcium channel blocker (CCB). However, as the effect of the CYP3A4*22 allele was only recently reported, these authors did not consider this variable as a potential predictive factor for tacrolimus CL/F.

Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients

Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients. Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied were determined by direct sequencing using a validated automated genetic analyzer. A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1). This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients

Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p<0.001) and 1.5-fold (p=0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7×(age/50)(-0.78)×2.03 (CYP3A5 expressers)×1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.

The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

The aims of this study were to determine the population pharmacokinetics of tacrolimus in Chinese adult liver-transplant recipients and to identify factors that may account for this variability. Tacrolimus dose and blood concentrations, along with clinical data, were collected retrospectively from 262 liver-transplant recipients. Data were analyzed using a nonlinear mixed-effects modeling method. A 1-compartment model with first-order absorption and elimination was selected as the base model. The influence of the following parameters were explored: (1) demographic characteristics, (2) biochemical and hematological laboratory test results, (3) surgery parameters, and (4) commonly used comedications. The typical values (interindividual variability percent coefficient of variation) for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 20.9 L h (23.8%) and 808 l (70.4%), respectively. The residual variability was 33.6%. Finally, the 4 covariates that showed a strong correlation with CL/F in this study were daily dose, hematocrit, total plasma protein, and the coadministration of sulfonylureas. CL/F was reduced significantly with sulfonylureas cotherapy, higher hematocrit levels, and elevated total protein. Moreover, CL/F increased nonlinearly with larger daily doses of tacrolimus. Concurrent therapy with sulfonylureas influenced tacrolimus CL/F in liver transplantation patients. These results and model will help clinicians to optimize tacrolimus regimens in Chinese liver transplantation patients.

Population Pharmacokinetics and Bayesian Estimation of Tacrolimus Exposure in Renal Transplant Recipients on a New Once-Daily Formulation

Advagraf is a new extended-release once-daily formulation of tacrolimus, a potent immunosuppressant widely used in renal transplantation. The aims of his study were (i) to develop a population pharmacokinetic model for once-daily tacrolimus in adult renal transplant patients; and (ii) to develop a Bayesian estimator able to reliably estimate individual pharmacokinetic parameters and exposure indices. Full pharmacokinetic profiles obtained from 41 adult renal transplant patients who had been switched from ciclosporin to a single daily dose of the new once-daily tacrolimus formulation for more than 6 months were analysed. Tacrolimus concentrations were measured using validated turbulent flow chromatography-tandem mass spectrometry methods. Population parameters were computed using nonlinear mixed-effect modelling software (NONMEM Version VI). The patients were randomly divided into (i) a model-building test group (n = 29); and (ii) a validation group (n = 12). Population pharmacokinetic analysis was performed to estimate the effects on tacrolimus pharmacokinetics of demographic characteristics (sex, bodyweight, age), drug interaction with prednisolone, laboratory test results (the haematocrit, haemaglobin level and serum creatinine level) and cytochrome P450 (CYP) 3A5 (CYP3A5) genetic polymorphism. The population pharmacokinetic model was further refined by taking into account all of the data from the 41 patients, and the final model was validated using a bootstrap and a visual predictive check. For Bayesian estimation, the best limited-sampling strategy was determined on the basis of the D-optimality criterion and validation performed in the validation group. The trapezoidal area under the whole-blood concentration time curve from 0 to 24 hours (AUC(24)) of tacrolimus varied by up to 50% for the same trough concentration value. The pharmacokinetics of once-daily tacrolimus were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase. The CYP3A5 genotype was the only covariate retained in the final model. The apparent clearance of tacrolimus was 2-fold higher in expressers (with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes) than in non-expressers (with the CYP3A5*3/*3 genotype). This factor explained around 25% of the interindividual variability in the apparent clearance. A posteriori Bayesian estimation allowed accurate prediction of the AUC(24) of once-daily tacrolimus, using just three sampling times (0, 1 and 3 hours post-dose) with a nonsignificant mean bias of 0.7% (range 16-20%) and good precision (root mean square error 9%). Population pharmacokinetic analysis of once-daily tacrolimus in renal transplant recipients resulted in identification of the CYP3A5*1/*3 genotype as a significant covariate on the apparent clearance of tacrolimus, and the design of an accurate maximum a posteriori Bayesian estimator based on three blood concentration measurements and this covariate. Such a tool could be helpful for comparing different exposure indices or different target levels. It could contribute to improvement of the efficacy and tolerability of once-daily tacrolimus in some patients.

Time of Drug Administration, CYP3A5 and ABCB1 Genotypes, and Analytical Method Influence Tacrolimus Pharmacokinetics: A Population Pharmacokinetic Study

Tacrolimus (TAC) pharmacokinetics are characterized by a very high variability that complicates its therapeutic use. The aims of this study were: 1) to identify and model the effect of demographic, clinical, and genetic factors and time of drug administration on TAC pharmacokinetic variability; and 2) to assess the influence of the analytical method by modeling the TAC blood concentrations measured simultaneously by microparticle enzyme immune assay (MEIA) and liquid chromatography-tandem mass spectroscopy. Data from 19 renal transplant candidates were analyzed. A total of 266 blood samples were analyzed for TAC by both techniques. Linear regression and Bland and Altman analyses were performed to compare TAC blood concentrations obtained with MEIA and liquid chromatography-tandem mass spectroscopy. A population pharmacokinetic analysis was performed. As expected, blood concentrations obtained by MEIA were higher than those obtained by liquid chromatography-tandem mass spectroscopy. A two-compartment model with first-order absorption and elimination best fit TAC blood concentrations. An exponential model was used to describe the interindividual and interoccasion variability and a mixed model was retained for the residual variability. A supplementary proportional term was necessary for the residual error in case of TAC blood concentrations determined by MEIA. The following covariates were retained in the final model: time of drug administration on the absorption rate constant and CYP3A5 and ABCB1 genotypes on the TAC apparent clearance. All parameter estimates had reliable values. The final model was found to be stable and generated parameters with good precision. The validation of the final model by bootstrapping (2000 bootstraps), case deletion diagnostics, crossvalidation, and visual predictive check (1000 simulated subjects) gave satisfactory results. This is the first population pharmacokinetic study confirming the chronopharmacokinetics of TAC and showing an effect of ABCB1 genotype and analytical method on TAC pharmacokinetics. These results may be helpful for TAC dose individualization.

Population pharmacokinetics of tacrolimus and CYP3A5, MDR1 and IL-10 polymorphisms in adult liver transplant patients

Tacrolimus, an immunosuppressant widely used after liver transplantation, is characterized by a large inter-individual variability in its pharmacokinetics. The aim of this study was to perform population pharmacokinetic analysis of oral tacrolimus in liver transplant recipients and clarify the potential role of CYP3A5, MDR1 and IL-10 genetic polymorphisms in the variability of population pharmacokinetic parameters. Tacrolimus blood concentration data (n = 1106) were collected from 104 full liver transplant patients and were analysed using a non-linear mixed-effects modelling program (nonmem). The CYP3A5*3, MDR1 G2677T/A and C3435T genetic polymorphisms were determined using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The IL-10 G-1082A variant was studied by allele-specific PCR method. The liver function in patients as indicated by the total bilirubin level (TBIL) and different CYP3A5*3 genotypes in donors (CYPD) and recipients (CYPR) were observed to influence tacrolimus pharmacokinetic parameter of apparent clearance (Cl/F). The final regression model can be expressed as Cl/F = 15.9 - 1.88 TBIL + 7.65 CYPD + 7.00 CYPR. The relative standard errors (%RSE) of the parameter estimation were lower than 30% and the residual variability of tacrolimus trough blood concentration was 2.81 ng/mL. No significant effect of MDR1 and IL-10 polymorphisms was observed on population pharmacokinetic parameter of tacrolimus within 175 days after liver transplantation. The TBIL in patients and CYP3A5*3 genetic polymorphism in both donors and recipients contribute to the inter-individual variability of oral tacrolimus apparent clearance in Chinese adult liver transplant patients.

Factors Affecting the Apparent Clearance of Tacrolimus in Korean Adult Liver Transplant Recipients

To identify the factors affecting tacrolimus apparent total body clearance (Cl/F [F = bioavailability]) in adult liver transplant recipients. Population pharmacokinetic analysis using data from a retrospective chart review. University-affiliated hospital in Seoul, South Korea. Fifty-one adult liver transplant recipients who had received tacrolimus after transplantation. Data on 35 adult liver transplant recipients for model building and 16 patients for model validation were obtained retrospectively. Population average parameter estimates of Cl/F and apparent volume of distribution (V/F) were sought by using the nonlinear mixed-effect model (NONMEM) program. A number of clinical covariates were screened for their influence on these pharmacokinetic parameters. The final optimal population model related Cl/F to total bilirubin, early (< or = 3 days) and late (> 35 days) postoperative days, international normalized ratio (INR), and graft:recipient weight ratio (GRWR). The NONMEM estimates indicated that the Cl/F of tacrolimus was decreased in patients with a small graft, hyperbilirubinemia, and a high INR. In addition, the Cl/F of tacrolimus almost doubled 4 days after transplantation, but decreased with an increase in duration of therapy after day 35. Mean prediction error and mean absolute prediction error were 0.26 and 3.78 ng/ml, respectively, for the validation sample. A final analysis in all 51 patients, which consisted of 1775 blood samples for concentration measurements, identified the following regression model: Cl/F (L/hr) = (0.36 + 2.01/POD * L) * TBIL(-0.23 (TBIL = 1 if TBIL level < or = 1.2 mg/dl, otherwise TBIL = TBIL level)) *49((if POD < or = 3 days)) * 0.75((if INR > 1.4)) * 0.86((if GRWR < or = 1.25%)) * WT, where L was 1 if postoperative day (POD) was greater than 35 days, otherwise L was 0; V/F was 568 L, TBIL was total bilirubin, and WT was body weight. The interindividual variabilities (coefficients of variation) in Cl/F and V/F were 35.35% and 68.12%, respectively. The residual variability was 3.14 ng/ml. These findings could be useful to the health care provider for adjustment of tacrolimus dosage in adult liver transplant recipients with various clinical factors.

Population Pharmacokinetic Estimation of Tacrolimus Apparent Clearance in Adult Liver Transplant Recipients

The goal was to study the factors affecting tacrolimus apparent clearance (CL/F) in adult liver transplant recipients. Tacrolimus dose and concentration data (n = 694) were obtained from 67 liver transplant recipients (22 female and 45 male), and the data were analyzed using a nonlinear mixed-effect modeling (NONMEM) method. A 1-compartment pharmacokinetic model with first-order elimination, an absorption rate constant fixed at 4.5 hours, and first-order conditional estimation was used to describe tacrolimus disposition. The predictive performance of the final model was evaluated using data splitting and assessing bias and precision of the estimates. The population estimate of tacrolimus CL/F and apparent volume of distribution (V/F) were found to be 21.3 L/h (95% confidence interval, CI, 18.0-24.6 L/h) and 316.1 L (95% CI 133-495 L), respectively. Neither patient's age, weight, gender, nor markers of liver function influenced tacrolimus CL/F. The final model was TVCL = 21.3 + 9.8 x (1 - HEM) + 3.4 x (1 - ALB) - 2.1 x (1 - DIL) - 7.4 x (1 - FLU), where TVCL, typical estimate of apparent clearance, HEM = 0 if hematocrit <35%, otherwise 1; ALB = 0 if albumin <3.5 g/dL, otherwise 1; DIL = 0 if diltiazem is coadministered, otherwise 1; FLU = 0 if fluconazole is coadministered, otherwise 1. This study identified the factors that significantly affect tacrolimus disposition in adult liver transplant recipients during the early posttransplantation period. This information will be helpful to clinicians for dose individualization of tacrolimus in liver transplant recipients with different clinical conditions including anemia or hypoalbuminemia or in those patients receiving diltiazem or fluconazole.

Case report of unchanged tacrolimus clearance in a hypoxemic pediatric liver transplant recipient with hepatopulmonary syndrome

Abstract Reductions in hepatic oxygen supply may reduce the oxidative metabolism of drugs, including tacrolimus. We encountered a patient (2.3-year-old girl) with hypoxemia [arterial oxygen tension (PaO2) 40.9 mmHg in room air] due to hepatopulmonary syndrome who had undergone living related liver transplantation. After transplantation, tacrolimus was initially administered by continuous intravenous infusion, and her PaO2 was maintained at more than 50 mmHg [72.8 ± 10.4 (SD) mmHg] by oxygen supplementation. Apparent clearance of tacrolimus (calculated as: the infusion rate of tacrolimus/blood concentration) in the patient (0.075 1/h per kg) was comparable to those of non-hypoxemic control pediatric cases (0.092 ± 0.014 1/h per kg, n= 7, mean age 2.2 years, PaO2 149.2 ± 41.5 mmHg), except for the acute decline in the early period after transplantation. These findings suggest that the reduction in tacrolimus clearance is negligible when arterial oxygen tension is maintained at more than 50 mmHg, even in patients with hypoxemia.

Case report of unchanged tacrolimus clearance in a hypoxemic pediatric liver transplant recipient with hepatopulmonary syndrome

Reductions in hepatic oxygen supply may reduce the oxidative metabolism of drugs, including tacrolimus. We encountered a patient (2.3-year-old girl) with hypoxemia [arterial oxygen tension (PaO2) 40.9 mmHg in room air] due to hepatopulmonary syndrome who had undergone living related liver transplantation. After transplantation, tacrolimus was initially administered by continuous intravenous infusion, and her PaO2 was maintained at more than 50 mmHg [72.8+/-10.4 (SD) mmHg] by oxygen supplementation. Apparent clearance of tacrolimus (calculated as: the infusion rate of tacrolimus/blood concentration) in the patient (0.075 l/h per kg) was comparable to those of non-hypoxemic control pediatric cases (0.092+/-0.014 l/h per kg, n=7, mean age 2.2 years, PaO2 149.2+/-41.5 mmHg), except for the acute decline in the early period after transplantation. These findings suggest that the reduction in tacrolimus clearance is negligible when arterial oxygen tension is maintained at more than 50 mmHg, even in patients with hypoxemia.