Tacrolimus Clearance Research Articles

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

We aimed to (i) develop a population pharmacokinetic model of tacrolimus in Chinese lung transplant recipients and (ii) propose model-based dosing regimens for individualized treatment. We obtained 807 tacrolimus steady-state whole blood concentrations from 52 lung transplant patients and genotyped CYP3A5*3. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to determine the initial dosing regimens. Tacrolimus pharmacokinetics was described by a one-compartment model with first-order absorption and elimination processes. In CYP3A5*3/*3 70-kg patients with 30% hematocrit and voriconazole-free therapy, the mean estimated apparent clearance was 13.1 l h−1 with 20.1% between-subject variability, which was lower than that in Caucasian lung transplant patients (17.5–36.5 l h−1). Hematocrit, postoperative days, tacrolimus daily dose, voriconazole concomitant therapy, and CYP3A5*3 genotype were identified as significant covariates for tacrolimus clearance. To achieve target trough concentration (10–15 ng ml−1) on the 8th day post-transplant, a higher initial dosage than the current regimen of 0.04 mg kg−1 every 12 h is recommended for CYP3A5*1/*3 patients without voriconazole concomitant therapy. Given the nonlinear kinetics of tacrolimus and large variability, population pharmacokinetic model should be combined with therapeutic drug monitoring to optimize individualized therapy.

Relationship Between Change Rate of Tacrolimus Clearance During Continuous Intravenous Infusion and Recipient Recovery at an Early Stage After Living Donor Liver Transplantation.

Tacrolimus clearance (CL) is significantly altered according to recovery of liver function at an early stage after living donor liver transplantation (LDLT). In this study, we aimed to examine the impact of the change rate from postoperative day (POD) 1 in CL (ΔCL) of tacrolimus during continuous intravenous infusion (CIVI) on recipient recovery. A tacrolimus population pharmacokinetic model on POD1 after LDLT was developed using Phoenix NLME 1.3. The CLPOD1 was calculated using the final model. The CLPOD4-7 was calculated by dividing total daily tacrolimus dose by the area under the concentration-time curve from 0 to 24h. Data were obtained from 57 LDLT recipients, along with 540 points (177 points on POD1, 363 points on POD4-7) of tacrolimus whole blood concentrations at CIVI. The median tacrolimus CL decreased from POD1 to POD4 (from 2.73 to 1.40L/h) and was then stable until POD7. Stepwise Cox proportional hazards regression analyses showed that the graft volume (GV)/standard liver volume (SLV) ratio (GV/SLV) and the tacrolimus ΔCLPOD6 were independent factors predicting early discharge (within 64days median value) of recipients after LDLT [hazard ratio (HR) = 1.041, P = 0.001 and HR = 1.023, P = 0.004]. The tacrolimus ΔCL during CIVI immediately after LDLT in each recipient was a useful indicator for evaluation of recovery at an early stage after LDLT.

Population pharmacokinetics model and initial dose optimization of tacrolimus in children and adolescents with lupus nephritis based on real-world data.

The present study aimed to establish a population pharmacokinetics model of tacrolimus and further optimize the initial dosing regimen of tacrolimus in pediatric and adolescent patients with lupus nephritis (LN). Pediatric and adolescent patients with LN were recruited between August 2014 and September 2019 at the Children's Hospital of Fudan University (Shanghai, China). Relevant information was used to set up a population pharmacokinetics model with a Nonlinear Mixed Effect Model and the initial dosage regimen was simulated with the Monte Carlo method. Body weight and co-administration of wuzhi capsule were indicated to influence tacrolimus clearance in pediatric and adolescent patients with LN, and at the same body weight, the rate of tacrolimus clearance in patients without vs. with co-administration of wuzhi capsule was 1:0.71. In addition, in patients who were not administered wuzhi capsule, an initial dosage regimen of 0.15 mg/kg/day was recommended for a body weight of 10-23 kg and 0.10 mg/kg/day for 23-60 kg; in patients who were administered wuzhi capsule, an initial dosage regimen of 0.10 mg/kg/day was recommended for a body weight of 10-23 kg and 0.05 mg/kg/day for 23-60 kg. To the best of our knowledge, the present study was the first to establish a population pharmacokinetics model of tacrolimus in order to determine the optimal initial dosage regimen of tacrolimus in pediatric and adolescent patients with LN.

Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics

ABSTRACT Background The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics. Methods Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus. Results Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended. Conclusions The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ.

Tacrolimus Levels after Direct Acting Anti-Viral Therapy in Hepatitis C Heart Transplantation

Hepatitis C (HCV) organs have been increasingly utilized in solid organ transplantation since the advent of curative direct acting anti-viral (DAA) therapy. Despite the adoption of this strategy, many unanswered questions remain regarding the management of immunosuppression. In two small case series of liver transplant recipients, tacrolimus concentrations have been shown to decrease with clearance of HCV viremia. We seek to describe our experience and clinical implications in our cardiac transplant population. We adopted the strategy of HCV cardiac transplantation followed by curative treatment in February of 2018. We analyzed the change in tacrolimus levels after DAA therapy in those who developed viremic HCV after receiving an HCV organ. Immunosuppression regimens were not altered for these patients from standard of care, which includes no induction therapy, corticosteroid taper by 6 months, and tacrolimus and mycophenolate mofetil as tolerated. Drug levels of tacrolimus were collected, as were clinical outcomes inclusive of infection, rejection and death. Twenty of twenty six NAT+/HCV+ patients experienced a decrease in tacrolimus levels with treatment, from a mean of 11.6 to a mean of 6.5 after HCV treatment. This decrease occurred towards the end of treatment and did not correspond with changes in tacrolimus dosing or other immunosuppressive agents. When compared to the non-HCV transplant population (n=37), no change in outcomes were observed. Treatment of HCV after transplantation may be correlated with increased metabolism, resulting in more rapid clearance of tacrolimus. Careful monitoring of drug levels and graft function is recommended as HCV organs are increasingly utilized. Further investigation into the clinical implications of these metabolic changes is warranted.

CYP3A5 Polymorphisms and Conversion to Once-Daily, Extended-Release Tacrolimus in Lung Transplant (LTx)

Calcineurin inhibitors have a narrow therapeutic index and are associated with significant inter- and intra-patient variability. The pharmacokinetic response to immunosuppressive drugs, and their intestinal absorption, may be affected by genetic polymorphisms of CYP3A4/3A5, as well as the low bioavailability and high fluctuation of twice-daily, immediate-release tacrolimus. Patients with CYP3A5 expressor genotypes (CYP3A5*1/*1 and *1/*3) metabolize substrates, such as tacrolimus, more rapidly than CYP3A5 non-expressors and have a higher rate of tacrolimus clearance. The frequency of alleles varies widely across different race and ethnic populations. In the general population, ∼90% of Caucasian patients are non-expressors (CYP3A5*3/*3), while ∼70% of African-American patients are expressors of CYP3A5*1. Once-daily, extended-release tacrolimus (Envarsus® XR) utilizes decreased drug particle size resulting in improved absorption, and has shown increased bioavailability, reduced Cmax, and non-inferior efficacy and safety in both de-novo and stable kidney transplant recipients. Data in LTx is lacking. We performed 50 lung transplants between November 2017 and April 2019. We identified a subset of patients who had consistently subtherapeutic levels despite increases in tacrolimus dose, and who required high doses to achieve goal trough levels. Cmax levels were measured to confirm inadequate exposure if patients were admitted at the time. Cmax levels were found to be consistently low, despite ensuring compliance. We suspected CYP3A5 genotype polymorphisms in 8 patients who required >8 mg/day of oral tacrolimus (or equivalent sublingual dose, using a 1:2 conversion). 7 of 8 patients were of African-American race/ethnicity and were CYP3A5 expressors (*1/*1 or *1/*3). After conversion to once-daily, extended-release tacrolimus, patients consistently achieved tacrolimus levels in therapeutic range. This is the first observational data assessing the frequency of CYP3A5 polymorphisms in LTx, and the feasibility of using extended-release tacrolimus to achieve therapeutic levels. Further studies are needed to assess patient and graft survival, freedom from BOS, effect of drug-drug interactions, and if any renal-protective benefit exists in this population.

Population Pharmacokinetic Analysis of Tacrolimus in Adult Chinese Patients with Myasthenia Gravis: A Prospective Study.

Tacrolimus isa widelyused immunosuppressive agent with narrow therapeutic window. Nowadays, tacrolimushasgainedacceptance as atherapeutic option in myasthenia gravis (MG) treament,however, little is known aboutits pharmacokineticcharacteristicsin MGpopulation. In this study, we aimed to investigate the population pharmacokinetic(PopPK) of tacrolimus in patients with MGand to develop model-informed dosing regimens. Trough concentrations of tacrolimus (267 measurements) and cytochrome P450 (CYP) genotypes were determined in 97 Chinese adults. The non-linear mixed-effects model was used for PopPK modeling. Monte Carlo simulations based on the established model were employed to design dosing regimens. The PopPK model was described using a one-compartment model with first-order absorption and elimination. The mean apparent clearance (CL/F) of tacrolimus was 17.1L/h, with a between-subject variability of 20.1%. Covariate screening of demographic characteristics, blood test results, co-medications, and CYP3A5*3 or CYP3A4*1G polymorphisms showed that the CYP3A5*3 genotype and co-administration of a Wuzhi capsule significantly affected tacrolimus CL/F. For patients with the CYP3A5*3*3 allele, the required tacrolimus dose for 75% of subjects to achieve target trough concentrations of 4.8-15ng/mL was 2mg every 12h (q12h). For patients with the CYP3A5*1*1 allele, the required dose was 2mg tacrolimus q12h with a Wuzhi capsule, and for patients with the CYP3A5*1*3 allele, the required dose was 3mg of tacrolimus q12h or 4mg q24h co-administered with a Wuzhi capsule. This model could be employed to optimize individualized therapies for patients with MG.

SUN-342 UNUSUAL HIGH DOSE OF TACROLIMUS IN RENAL TRANSPLANT PATIENTS: A CASE SERIES

Tacrolimus, is an immunosuppressant, characterized by highly variable pharmacokinetics (PK) and a small therapeutic window, which make therapeutic drug monitoring (TDM) mandatory for maintaining adequate exposure. TDM allows dose adjustment in order to avoid graft rejection and tac-induced adverse effects, which are the most challenging after transplantation. Tacrolimus is metabolized specifically by the CYP3A isoenzyme: CYP3A4 and CYP3A5. Many single nucleotide polymorphisms (SNPs) such as CYP3A4*1B -392A>G, CYP34*22 15389C>T, and CYP3A5*3 6986A>G related to the expression levels of CYP enzymes may explain a part of the variability in tacrolimus PK. It is admitted that patients harboring the predominant CYP3A5*3, associated with enzymatic function loss, require roughly 50% lower tacrolimus doses than those with CYP3A5*1. CYP3A4*1B. Recently, it has been shown that CYP3A4*22 carriers had a lower clearance of tacrolimus (-16%). We describe herein two cases of renal transplant patients who have great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. It is a retrospective study reporting the case of 2 patients with difficulty in reaching the desired trough blood levels of tacrolimus. Our first patient is a 34-year-old man who received a living donor kidney transplant (his mother) on March 15, 2017. He was prescribed Tacrolimus at an initial dose of 14 mg/day divided every 12 hours (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration C0 was 5ng/ml. The dose was progressively increased reaching a daily dose of 22 mg divided every 12 hours with the trough blood concentration C0 = 6.4 ng/ml.CYP3A4 and CYP3A5 genotyping were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). The patient was heterozygous for the CYP3A5*3 allele (*1/*3) and homozygous for the CYP3A4*1B (*1B/*1B) and CYP3A4*22 alleles (*1/*1). So the patient was considered a high metabolizer, the reason behind the need for elevated doses of tacrolimus to achieve a therapeutic trough concentration. Our second patient is a 42-year-old man who received a living donor kidney transplant (his sister) on September 28, 2016. He was initially prescribed Tacrolimus at 12mg/day in two divided doses (0.12-0.15 mg/kg/day) in association with a corticosteroid and mycophenolate mofetil. The trough blood concentration (C0) was 3 ng/ml. The dose was then progressively increased reaching a daily dose of 20 mg/day. C0 was 4.1 ng/ml. The patient was homozygous for the three alleles (CYP3A5*1/*3, CYP3A4*1B/*1B, and CYP3A4*1/*1). Our patient is a CYP3A5 expressor and a CYP3A4*1B and CYP3A4*22 carrier, thereby making him a high metabolizer and requiring high doses of tacrolimus in order to achieve a therapeutic trough concentration. The present case series appears to confirm the main responsibility of the CYA3A4 and CYP3A5 genetic polymorphisms in determining the dose requirements of tacrolimus in renal transplant patients. Although pharmacogenetic analysis cannot substitute TDM, the availability of genotyping renders possible to better define the initial tacrolimus dosage.

Age-Related Trend in Tacrolimus Clearance Among Children Undergoing Stem Cell Transplantation

<h3>Background</h3> An optimization of tacrolims (TAC) treatment is a key to prevent graft-versus-host disease. Previous studies reported that a high clearance (CL) of TAC is a risk factor in adult with renal transplantation. However, there is limited information on the pharmacokinetics of TAC in children after hematopoietic stem cell transplantation (HSCT). The purpose of this study is to evaluate an age-dependent variation in CL of TAC. <h3>Methods</h3> We retrospectively analyzed CL of TAC in patients who underwent HSCT at the National Center for Child Health and Development in Japan from August 2006 to August 2019. There were four time points after HSCT to calculate CL of TAC; 17 hours after the start of TAC infusion (CLinitial), the first day at a steady state (CLss), 21 days after SCT (CL21), and the day before switch from intravenous infusion to oral administration (CLpre). We compared CL of TAC between children aged < 6 years and aged ≥ 6 years. TAC was infused intravenously at initial dosage of 0.02 mg/kg/day. For patients receiving voriconazole, initial dosage of TAC was adjusted to 0.01 mg/kg/day. <h3>Results</h3> A total number of 41 patients (age < 6 years; 25 patients, age ≥ 6years; 16 patients) were evaluated. Median age was 3 years (2 months - 18 years). Two patients recieved HSCT multiple time. Thirteen patients underwent HSCT for nonmalignant disease. CL of TAC in patients aged < 6 years old was significantly higher than aged ≥ 6years old at CLinitial, CLss, and CLpre.(CLinitial: 0.14 ± 0.08L/h/kg vs 0.08 ± 0.03L/h/kg (P=0.01), CLss: 0.06 ± 0.03L/h/kg vs 0.05 ± 0.02L/h/kg (P=0.04), CLpre: 0.06 ± 0.04L/h/kg vs 0.04 ± 0.02L/h/kg (P=0.03)) (Figure). The average duration was 5.4 days at the first steady state in both groups. In patients aged < 6 years old, rate of achieving the target range (10-15ng/mL) at CLss were lower than aged ≥ 6years old (76.0% vs 93.8% (p=0.045)), and 1.3 times of initial TAC dosage was needed at CLss for children aged < 6 years. <h3>Conclusion</h3> This study suggested that children aged < 6 years old need higher dosage to achieve therapeutic TAC level compared with children aged ≥ 6years old, especially at early phase of HSCT. In addition, careful TAC monitoring with consideration of age-related variation in clearance is required after pediatric HSCT.

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.

Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration with Wuzhi capsule.

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. Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non-linear mixed-effects modelling (NONMEM) analysis. 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 0.10mg/kg split into two doses was suitable for people with weights from 10 to 60kg 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, 0.15mg/kg split into two doses was appropriate for those with weights from 10 to 40kg and 0.10mg/kg split into two doses was appropriate for those with weights from 40 to 60kg. 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.

Optimization of initial dosing scheme of tacrolimus in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule

The present study aimed to optimize the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on population pharmacokinetics and pharmacogenomics.Demographic characteristics, concomitant medication, laboratory data, pharmacogenomics were collected to build the model and Monte Carlo was used to simulate the optimization of initial dosing scheme.Weight, the polymorphisms of CYP3A5, and concomitant medication of wuzhi-capsule were included into the covariates affecting tacrolimus clearance. In addition, with the same weight, there was difference in tacrolimus clearance in patients who carry CYP3A5*3/*3 and no coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and no coadministration of wuzhi-capsule, patients who carry CYP3A5*3/*3 and coadministration of wuzhi-capsule, patients who carry CYP3A5*1 allele and coadministration of wuzhi-capsule, and their clearance ratios were 1:1.5:0.697:1.0455, respectively. Based on the differences of clearance in the above cases, we simulated different dosing regimens and obtained the optimal initial dose in each case.The present study recommended the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule.

Comparison of the effect of direct-acting antiviral with and without ribavirin on cyclosporine and tacrolimus clearance values: results from the ANRS CO23 CUPILT cohort.

Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse. Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays. Sixty-seven mainly male patients (79%) were included, with a mean age of 57years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p =0.02) and lower haemoglobin during direct-acting antiviral treatment (p =0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range. Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels. NCT01944527.

Impact of body composition on pharmacokinetics of tacrolimus in liver transplantation recipients

1. There are still no studies examining the relationship between body composition and tacrolimus pharmacokinetics in liver transplantation recipients. We aimed to investigate the influence of body composition on tacrolimus pharmacokinetics in liver transplantation recipients.2. Body composition was measured in 80 patients who underwent liver transplantation at Tianjin First Central Hospital, China, between 2015 and 2018. Blood concentrations of tacrolimus were collected from therapeutic drug monitoring data. Pharmacokinetic model fitting and Bayesian estimation were performed using nonlinear mixed-effects modeling (NONMEM) and SPSS was used to examine the effect of body composition on tacrolimus pharmacokinetics.3. The apparent volume of distribution (V/F) and clearance (CL/F) of tacrolimus were 179 L and 15.4 L/h, respectively. In liver transplantation recipients with percentage body fat (PBF) ≥ 30%, the apparent V/F of tacrolimus is lower than that in liver transplantation recipients with PBF < 30% at 1 week after liver transplantation.4. The new finding is important due to the severe adverse effects of tacrolimus. In clinical practice, an effective dosage adjustment of tacrolimus may need to be considered in patients with PBF ≥ 30% at 1 week after liver transplantation.

A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype.

In adult patients after living‐donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically‐based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living‐donor liver transplantation. The clearance was about 1.35‐fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7‐fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically‐based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.

Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients.

This review examines what is currently known about the pharmacokinetics and pharmacodynamics of commonly prescribed immunosuppressant medicines, tacrolimus, cyclosporine, mycophenolate and prednisolone, in elderly renal transplant recipients, and reported patient outcomes in this cohort. Renal transplantation is increasing rapidly in the elderly, however, currently, long-term patient outcomes are relatively poor compared to younger adults. Some studies have suggested that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors tacrolimus and cyclosporine; with one study reporting up to 50% reduction in tacrolimus exposure in the elderly. Elderly transplant recipients do not appear to have higher dosage-adjusted exposure to mycophenolic acid (MPA). The effects of ageing on the pharmacokinetics of prednisolone are unknown. Only one study has examined how aging effects drug target enzymes, reporting no difference in baseline inosine 5'-monophosphate dehydrogenase (IMPDH) activity and MPA-induced IMPDH activity in elderly compared to younger adult renal transplant recipients. In elderly transplant recipients, immunosenescence likely lowers the risk of acute rejection, but increases the risk of drug-related adverse effects. Currently, the three main causes of death in elderly renal transplant recipients are cardiovascular disease, infection and malignancy. One study has showed that renal transplant recipients aged over 65 years are seven times more likely to die with a functioning graft compared with young adults (aged 18-29 years). This suggests that an optimal balance between immunosuppressant medicine efficacy and toxicity is not achieved in elderly recipients, and further studies are needed to foster long-term graft and patient survival. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established.

Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection.

To (i) describe tacrolimus (TAC) pre-dose concentrations (C0), (ii) calculate apparent oral TAC clearance (CL/FHCT) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C0 or high mean CL/FHCT are associated with an increased risk of rejection episodes early after lung transplantation. TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C0) was measured, and CL/FHCT was determined using non-compartmental analysis. The associations between TAC C0 and CL/FHCT and rejection status were explored using repeated measures logistic regression. Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/FHCT 6.8 (4.2-15.9)Lh-1, and the median C0 12.7 (9.9-16.6)μgL-1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/FHCT in all patients over time: CL/FHCT 14 (5.4-23) at week 3, CL/FHCT 7.7 (4.5-12) at week 6 and CL/FHCT 3.9 (2.4-11)Lh-1 at week 12 (p <0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p =0.02), and greater mean CL/FHCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p =0.04). Monitoring TAC C0, HCT and CL/FHCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.

Dosage Optimization Based on Population Pharmacokinetic Analysis of Tacrolimus in Chinese Patients with Nephrotic Syndrome.

The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients. Nephrotic syndrome patients (>16years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus. The mean apparent clearance (CL/F) of tacrolimus was 13.4L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers. A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.

A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients.

AimsThe aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient.MethodsData on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed‐effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates.ResultsA total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two‐compartment model. The mean absorption rate was 3.6 h−1, clearance was 23.0 l h–1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: Dosemg=222nghml–1*22.5lh–1*1.0ifCYP3A5*3/*3or1.62ifCYP3A5*1/*3orCYP3A5*1/*1*1.0ifCYP3A4*1or unknownor0.814ifCYP3A4*22*Age56−0.50*BSA1.930.72/1000Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model.ConclusionsFor a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.

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.