Tacrolimus Blood Concentrations Research Articles

Development and Validation of a Nomogram for Predicting Subtherapeutic Tacrolimus Blood Levels in Renal Transplant Recipients: A Multivariate Logistic Regression Analysis.

Development and Validation of a Nomogram for Predicting Subtherapeutic Tacrolimus Blood Levels in Renal Transplant Recipients: A Multivariate Logistic Regression Analysis.

Plasma Versus Whole Blood Tacrolimus Concentrations and Health-Related Quality of Life in Kidney Transplant Recipients

Background/Objectives: Tacrolimus dosing traditionally relies on therapeutic drug monitoring in whole blood, while assessment in plasma may better reflect its effect and reveal overdosing impacting health-related quality of life (HRQoL). Methods: In this cross-sectional study, 898 kidney transplant recipients (KTRs) who were at least 12 months post-transplantation were included. Plasma and whole blood tacrolimus concentrations were compared using Passing–Bablok regression analyses and Bland–Altman plots. Furthermore, the relationship with daily tacrolimus dose and with HRQoL (mental component summary (MCS), physical component summary (PCS)) was explored using linear regression by comparing standardized coefficients. Lastly, mediation analyses explored the effect of various tacrolimus-related side effects on the association between tacrolimus concentrations and HRQoL. Results: Comparison of the methods revealed a constant bias and a slight proportional bias between whole blood and plasma tacrolimus concentrations. The Bland–Altman plots indicated poor agreement with a statistically significant ratio difference (p < 0.001). Both whole blood and plasma concentrations were significantly associated with daily tacrolimus dose (both p < 0.001). Compared to whole blood tacrolimus concentrations, plasma tacrolimus concentration showed a strong negative association with worse HRQoL (PCS: st. β = −0.12, p = 0.01; MCS: st. β = −0.14, p < 0.001). The associations between plasma tacrolimus concentrations and HRQoL were mediated by fatigue severity (proportion mediated on PCS: 67.8%, MCS: 59.5%) and reduced kidney function (proportion mediated on PCS: 16.7%, MCS: 12.9%). Conclusions: In conclusion, compared with whole blood tacrolimus concentrations, plasma tacrolimus concentrations exhibited a negative association with HRQoL in KTRs. Consequently, therapeutic drug monitoring using plasma tacrolimus concentrations may reduce the occurrence of tacrolimus-related toxicity.

Robust UPLC-MS/MS Method With Acetonitrile for Precise Intracellular Quantification of Tacrolimus in PBMCs: A Step Toward Clinical Integration.

Monitoring whole blood tacrolimus concentrations is standard in clinical practice; however, it may not fully reflect its therapeutic effects, as tacrolimus primarily acts within lymphocytes. While various intracellular quantification methods have been developed, many involve complex procedures such as evaporation, reconstitution, or specialized tools (e.g., magnetic beads, online solid-phase extraction), limiting their accessibility. This study aimed to develop and validate a streamlined, sensitive method for measuring intracellular tacrolimus concentrations using 5×105 peripheral blood mononuclear cells (PBMCs). Tacrolimus concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PBMCs were aliquoted into 50 μL volumes containing 5×105 cells and prepared via acetonitrile-based protein precipitation. Chromatographic separation was performed using a Luna C18 column with a gradient mobile phase consisting of water with 20 mM ammonium acetate, 0.1% formic acid, and methanol at a flow rate of 0.4 mL/min. The method demonstrated excellent linearity between 0.1 and 25 ng/mL, corresponding to intracellular concentrations of 1-250 pg/5×105 cells (r2 = 0.999). Intra- and interday accuracy ranged from 98.1% to 109.8%, with precision between 2.08% and 8.70% across validation runs. Extraction recovery was high (93.0%-97.2%), with minimal matrix effects (100.9% at low QC and 111.6% at high QC). This validated LC-MS/MS method provides a rapid, reliable, and sensitive approach for pharmacokinetic studies and clinical applications, facilitating intracellular tacrolimus monitoring in transplant patients.

Effect of Wuzhi Capsule (WZC) on the Pharmacokinetics of Tacrolimus in Renal Transplantation Recipients.

Previous studies have shown that WZC can increase tacrolimus blood concentration when co-administered. However, limited knowledge exists regarding the pharmacokinetics of both tacrolimus and the bioactive lignans in WZC when administered simultaneously in renal transplantation patients. This study aimed to investigate the pharmacokinetics of tacrolimus and multiple bioactive lignans in Wuzhi capsule (WZC) when co-administered with 5 bioactive components in renal transplantation recipients. The objective of this study was to develop a method for simultaneous quantification of tacrolimus and multiple bioactive lignans in WZC using liquid-liquid extraction followed by LC-MS/MS analysis. A liquid-liquid extraction method combined with LC-MS/MS analysis was developed for simultane-ous quantification of tacrolimus and multiple bioactive lignans in WZC. Human whole blood samples were analyzed, and the accuracy and precision of the method were evaluated. The developed method showed good linearity and accuracy for the quantification of tacrolimus and bioactive lignans in WZC. Pharmacokinetic analysis revealed significant effects of WZC co-administration on both V/F and CL/F in renal transplantation patients. This study demonstrated that simultaneous administration of WZC had notable effects on the pharmacokinetics of tacrolimus and bioactive lignans in renal transplantation patients. The developed method proved to be reliable and sensitive for determining the whole blood concentrations of tacrolimus and WZC, making it suitable for pharmacokinetic studies in transplant patients.

Pre-transplant tacrolimus fluctuations predict BK virus infection risk in kidney transplants.

BK virus (BKV) infection is a significant complication in kidney transplant recipients, potentially leading to graft loss. The relationship between pre-transplant tacrolimus (TAC) pharmacokinetics and BKV infection risk remains unclear. This study aimed to investigate whether pre-transplant TAC blood concentration fluctuations are associated with BKV infection risk. We conducted a retrospective study of 135 living donor kidney transplant recipients at Hirosaki University between 2006 and March 2024. Patients were divided into BKV-infected (BKV) and non-infected (non-BKV) groups. TAC blood concentrations were measured at 4 points, including 0 h (2 h before TAC administration), 4, 6, and 12 h on the day before transplantation. Changes in TAC concentration from baseline (0h) were calculated for each time point. The concentration/dose (C0/D) ratio was used as an indicator of TAC metabolism rate. During a median follow-up of 54months, 29 recipients developed BKV infection. The BKV group had significantly older donors and showed a significantly larger decrease in TAC concentration at 12h compared to the non-BKV group (-1.5 vs. 0ng/mL, P = 0.008). There was no significant difference in pre-transplant C0/D ratios between the two groups. A decrease of ≥ 1.5ng/mL at 12h was identified as a significant risk factor for BKV infection (hazard ratio: 2.44, 95% confidence interval: 1.11-5.32, P = 0.026) in a propensity score-based inverse probability of treatment weighting multivariate Cox proportional hazards analysis. Pre-transplant TAC blood concentration fluctuations, particularly a large decrease at 12h from baseline, may be associated with increased BKV infection risk.

Maternal and infant outcomes of pregnancy after kidney transplantation: a retrospective cohort study

PurposeTo investigate the effect of postoperative pregnancy on maternal-infant outcomes and transplanted kidney function in kidney transplantation (KT) recipients.MethodsOur study included 104 KT recipients and 104 non-KT women who delivered at four hospitals affiliated with Zhejiang University School of Medicine from December 2015 to November 2023.ResultsIn the KT group, kidney function showed a downward trend after delivery, and most patients recovered normal kidney function within 6 months postpartum. Tacrolimus blood concentration during pregnancy averaged (6.1 ± 1.4) μg/L, increasing to (7.1 ± 2.6) μg/L on the second day after delivery, indicating an upward trend in postpartum concentrations. Compared to the non-KT group, the KT group had higher prevalences of gestational hypertension (33.7% vs. 3.3%), gestational diabetes mellitus (21.2% vs. 17.5%), intrahepatic cholestasis of pregnancy (5.8% vs. 1.7%), placental abruption (1.9% vs. 0.8%), and preterm birth rate (79.8% vs. 9.2%) but had a lower prevalence of fetal growth restriction (8.3% vs. 21.7%). Univariate analysis showed that pre-pregnancy estimated glomerular filtration rate (eGFR), penatal eGFR, gestational hypertension, and preeclampsia may influence neonatal outcomes. Binary logistic regression analysis showed that preeclampsia (odds ratio [OR] = 133.89, 95% confidence interval [CI]: 1.27–156.20, P = 0.031) and hypertension during pregnancy (OR = 5.81, 95% CI: 1.02–33.27, P = 0.048) were risk factors, and glomerular filtration rate during pregnancy (OR = 0.95, 95% CI: 0.90–0.99, P = 0.026) was a protective factor.ConclusionAlthough pregnancies in KT recipients are considered high-risk, the overall risks are manageable. Strengthening the management of KT recipients with reproductive intent is recommended to improve maternal and infant outcomes.

Correlation of renal function with intra-patient variability of tacrolimus concentration among recipients of renal transplants: a 10-year study.

Tacrolimus is one of the most commonly used basic immunosuppressants nowadays, but the high variability of tacrolimus blood concentration often leads to kidney transplant recipients frequently experiencing drug concentrations above or below the target concentration, resulting in renal toxicity or rejection of the transplanted kidney. The aim of this study is to explore the correlation of renal function with intra-patient variability (IPV) of tacrolimus blood concentration among recipients of renal transplants at 1-, 3-, 5-, and 10-year post-transplantation. Recipients of renal transplants who were treated with tacrolimus for immunosuppression at the Shanghai General Hospital between January 2001 and December 2009, and followed up until 2019 were included in this retrospective study. Demographic characteristics and laboratory investigation results at their 1-, 3-, 5-, and 10-year follow-up visits were collected from their hospital medical records. Patients were divided into a low or high IPV group based on the IPV of their tacrolimus concentrations. A total of 167 kidney transplant recipients were included in the study. At the 3-year follow-up visit, patients in the low IPV group had significantly lower blood urea nitrogen (BUN) (6.3±1.8 vs. 8.2±6.2 µmol/L, P=0.04), serum creatinine (Scr) (88.8±23.6 vs. 104.8±39.6 µmol/L, P=0.009), and blood uric acid (UA) (329.1±80.2 vs. 375.9±95.1 µmol/L, P=0.004), as well as significantly higher estimated glomerular filtration rate (eGFR) values than patients in the high IPV group. Blood UA levels were significantly lower in patients in the low IPV group than the high IPV group at the 10-year follow-up (362.7±92.6 vs. 398.5±105.2 µmol/L, P=0.042). There was no significant difference between the low and high IPV groups with respect to BUN, Scr, UA, or eGFR at the 1- and 5-year follow-up. Recipients of renal transplants with lower IPV in tacrolimus concentration appeared to have better renal function over time. Controlling IPV may contribute to improved renal outcomes post-transplantation.

Measurement of Whole Blood Tacrolimus Concentrations by LC-MS/MS and Immunoassay Methods: Influence of Immediate-Release vs Extended-Release Tacrolimus Formulations.

Therapeutic drug monitoring of the immunosuppressant tacrolimus is commonly performed by immunoassay or LC-MS/MS. Measurement biases between these methodologies have been characterized for immediate-release tacrolimus (IR-tac; Prograf) but have not been performed for extended-release formulations such as Envarsus. These discrepancies can impact patient care, as appropriate dosing is required to maintain therapeutic concentrations and immunosuppression. Validation of a whole-blood LC-MS/MS method for the simultaneous quantification of tacrolimus and its major metabolite, desmethyl tacrolimus, was performed using traceable calibrators (tacrolimus, ERM-DA110a) and quality control (QC) material for tacrolimus and standard material for desmethyl tacrolimus. Tacrolimus concentrations were determined by LC-MS/MS and the ARCHITECT immunoassay in patients receiving either IR-tac or Envarsus for clinical care. External calibration curves for both tacrolimus and desmethyl tacrolimus were linear (R2 > 0.995), and the analytical measurement range (AMR) for tacrolimus spanned from 1.1 to 31.6 ng/mL. Calibrator/QC biases were within 15% of their spiked concentrations throughout the AMR, and within-run imprecision was <10%, except at the lower limit of quantification (n = 25). Between-run imprecision for low, mid, and high QC levels was ≤11% over a 2-week period (n = 5 days). Comparative biases between immunoassay and LC-MS/MS were significantly lower (P = 0.0074) for patients receiving Envarsus (n = 20 specimens) relative to patients receiving IR-tac (n = 32 specimens). Biases between immunoassay and LC-MS/MS tacrolimus measurements in patients receiving immediate-release vs extended-release formulations indicate that their distinct pharmacokinetic profiles impact measurement accuracy. These assay biases should be considered when interpreting tacrolimus concentration measurements.

Time in therapeutic range of tacrolimus in allogeneic hematopoietic stem cell transplant recipients is associated with acute graft-versus-host disease prophylaxis

Intra-patient variability in immunosuppressive blood drug concentrations is a potential biomarker in managing organ transplant patients. However, the association between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in preventing graft-versus-host disease remains unknown. In this study, we analyzed the relationship between the time in therapeutic range of tacrolimus blood concentrations and its efficacy in acute graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation. Eligible patients administered tacrolimus were categorized into two groups based on the grade of acute graft-versus-host disease, and propensity score matching was performed using graft-versus-host disease prophylaxis protocols and days to the disease onset to compare time in therapeutic range. In patients with tacrolimus blood concentration therapeutic range ≥ 10 ng/mL, time in therapeutic range during the first 4 weeks post-transplantation was significantly lower in the Grade II–III than in the Grade 0–I group. Among propensity score matching-extracted patients, the Grade II–III group had significantly lower time in therapeutic range during the first 2 and 4 weeks post-transplantation. Our results suggest that high time in therapeutic range early post-transplantation, particularly within 4 weeks, may avert the severity of acute graft-versus-host disease.

The effect of the use of omeprazole versus famotidine on the kidney transplant function: a randomized controlled study

Tacrolimus is metabolized in the liver with the participation of cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). Omeprazole, unlike famotidine, is a substrate and inhibitor of CYP2C19, CYP3A4, CYP3A5 enzymes. The aim of the study is to compare the effect of omeprazole and famotidine on the tacrolimus concentration and the kidney transplant function. A randomized study was conducted in 24 adult patients with stable kidney transplant function who received a standard triple immunosuppression regimen. Patients were assigned to the group I (n = 12) additionally receiving omeprazole (20 mg) or the group II (n = 12) receiving famotidine (20 mg). At the time of qualification and during follow-up visits, tacrolimus blood concentration and selected laboratory tests were performed. Statistical analysis was performed using the MedCalc system. The value of tacrolimus concentration in the blood increased after a year in the group I (7.27 ± 2.33 vs 9.20 ± 2.46 ng/mL, p = 0.0478). A reduction in tacrolimus dosage was observed after three years in the group I (3.56 ± 1.75 vs 2.78 ± 1.00 mg, p = 0.0440) and in the group II (2.72 ± 0.84 vs 2.10 ± 0.48 mg, p = 0.0051). There was significant difference in the percentage changes of glomerular filtration rate between the groups after 3 years of the study (− 5.56% vs 9.13%, p = 0.0343). Omeprazole significantly change the concentration of tacrolimus in the blood when administered together with tacrolimus after one year of observation. There was no effect of famotidine or omeprazole on the function of the kidney transplant. ClinicalTrials.gov identifier: NCT05061303.

Pharmacokinetic Interaction between Imatinib and Tacrolimus in Rats.

Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats. Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and Ndesmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry. After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and Cmax of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and Cmax of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC0-24 and AUC0-∞ of tacrolimus (P < 0.05). Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.

Innovative Personalized Medicine for Immunosuppressive Drugs Based on Novel Control Theory of Pharmacokinetics

Tacrolimus is widely recognized as an anti-rejection agent due to its immunosuppressive characteristics. It binds to the immunophilin FK506-binding protein (FKBP) and thus to calcineurin, and inhibits its activity. Tacrolimus' therapeutic concentration range in blood is narrow, and its pharmacokinetics are highly variable among individuals. First, because tacrolimus primarily distributes to red blood cells (RBCs), anemia and blood transfusions can cause fluctuations in tacrolimus blood concentrations. Variations in blood tacrolimus concentration significantly correlated with variations in RBC count, hemoglobin level, and hematocrit value, but not with variations in white blood cell or platelet counts. Interestingly, FKBP played an important role in tacrolimus distribution to RBCs. The effects of intracellular and extracellular FKBP levels on RBC distribution of tacrolimus in circulating blood were substantial. Secondly, proteins affecting pharmacokinetics can differ at the genetic level in their expression and functional potency. Genetic polymorphisms that influence tacrolimus pharmacokinetics have been reported. A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 (CYP) 3A5 is a particularly influential factor affecting tacrolimus pharmacokinetics in Japanese patients. CYP3A5 polymorphisms correlated with individual differences in tacrolimus blood concentration changes after starting continuous infusion in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In addition, CYP3A5*3 polymorphism also correlated with differences in the frequency of acute graft-versus-host disease (GVHD) development in allogeneic HSCT recipients.

A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus.

One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (Cmax) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.

Association between salivary microbiota and tacrolimus pharmacokinetic variability in kidney transplant

Kidney transplantation (KT) serves as a highly effective treatment for end-stage renal disease (ESRD). Nonetheless, the administration of tacrolimus, a commonly used immunosuppressant in KT, faces challenges due to the lack of dependable biomarkers for its efficacy and the considerable variability in tacrolimus pharmacokinetics (TacIPV). In this study, 183 saliva samples from 48 KT recipients under tacrolimus therapy, alongside 9 healthy control samples, were subjected to 16S rRNA sequencing. The analysis revealed significant differences in the composition of salivary microbiota among KT recipients, patients with ESRD, and healthy controls. Moreover, trough blood concentrations (C0) of tacrolimus were associated with alterations in microbiota composition. Notably, Capnocytophage consistently exhibited a negative correlation in both group-level and individual trends. Furthermore, distinct taxa were identified that effectively distinguished recipients with varying TacIPV, as demonstrated by a cross-validation random forest model (mean AUC = 0.7560), with Anaerolinea emerging as a prominent contributor to the classifier. These findings suggest that salivary microbiota is closely linked to tacrolimus C0 levels and could aid clinicians in differentiating KT recipients based on TacIPV.

Guiding the starting dose of the once-daily formulation of tacrolimus in "de novo" adult renal transplant patients: a population approach.

The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60years and younger. The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60years or younger would be highest, while CYP3A5*/1 non-carriers older than 60years would require the lowest doses.

Association of Therapeutic Monitoring of Tacrolimus with Laboratory Markers of Kidney Function in Receptors of Kidney Allograft

Introduction: Kidney transplantation is the most commonly performed type of transplant in Brazil. Tacrolimus is one of the primary drugs used in post-transplant immunosuppressive therapy, and one of its main adverse effects is nephrotoxicity. Laboratory tests to assess renal function are of great importance in monitoring post-kidney transplant patients, helping to diagnose events indicative of graft dysfunction. Objective: !e present study aimed to evaluate the association between laboratory changes in renal function and blood levels of tacrolimus in post-kidney transplant patients. Methods: Observational, analytical and cross-sectional study. !e results of blood levels of tacrolimus and measurements of urea, creatinine and estimated Glomerular Filtration Rate (eGFR) were analyzed, as well as the sociodemographic data of kidney transplant recipients followed at a university hospital who underwent laboratory tests between months from January 2021 to July 2022 in a period close to 1 year after the transplant. !e variables analyzed in the research were collected from the patient's medical records and subsequently analyzed; the statistical analyses considered p &lt; 0.05. !e project was approved by the Ethics Committee of the Walter Cantídio University Hospital under opinion number 5,436,434 and CAAE number 57396622.1.0000.5045. Results: !e sample was mainly composed of males, mixed race, with an average age of 51.5 years (SD ± 12.5) and from cities in the interior of Ceará. Regarding the percentage of patients with laboratory changes, 50.62% (n = 45) showed changes in tacrolimus blood levels. 56.79% (n = 46) had changes in serum creatinine levels, 49.38% (n = 40) had changes in serum urea levels, and 59.26% (n = 48) had altered eGFR. !e correlation analyses suggested a low signi#cance between variations of the variables studied. Conclusion: !e results indicate no relationship between variations in tacrolimus blood concentrations and the appearance of changes in the results of classic renal biomarkers at the end of the #rst year post-transplant. However, it is necessary to carry out new studies to understand better the impact of changes in blood levels of tacrolimus on the renal function of renal allograft recipients.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

Population pharmacokinetics study of tacrolimus in liver transplant recipients: a comparison between patients with or without liver cancer before surgery.

The main challenge for immunosuppressive therapy using tacrolimus in liver transplantation is the considerable variability in its oral bioavailability and the narrow treatment range. Many population pharmacokinetic (PopPK) models have been established to precisely estimate the PK variability of tacrolimus in liver transplant recipients. However, it remains unclear whether there is a significant difference in the PK behavior of tacrolimus between patients with or without liver cancer before surgery. Therefore, we aimed to compare the differences of PK parameters and simulate exposures of tacrolimus between populations preoperatively diagnosed with liver cancer or not by PopPK modeling. In total, 802 blood concentrations of tacrolimus from 196 patients (118 liver cancer and 78 non-liver-cancer samples) were included in this study. Demographic data and clinical parameters were integrated to perform a PopPK analysis using the nonlinear mixed-effects modeling approach. Potential covariates were evaluated by using a stepwise method. Goodness-of-fit plot and bootstrap were performed to assess the model stability and predictive performance. Simulations were introduced to optimize dosing regimens of both the liver cancer and non-liver-cancer groups according to the guidance. The PK of tacrolimus was best described by a one-compartment model with first-order absorption and linear elimination, with weight and direct bilirubin as the significant covariates. In the process of constructing the basic model, we tried to separately estimate the PK parameters in liver cancer and non-liver-cancer populations. The results showed that the PK parameters in the two populations were similar, and the individual variation in Ka in non-liver-cancer subjects was large. Hence, the final model did not distinguish between the two populations. Moreover, a minor increase of less than 10% was observed in the simulated exposure in the patients preoperatively diagnosed with liver cancer compared with that in non-liver-cancer groups. The established PopPK model was capable of optimizing tacrolimus dosing in whole populations who underwent liver transplantation. Although a minimal difference was found in tacrolimus exposure between the liver cancer and non-liver-cancer groups, more research is warranted to explore the differences between the two populations in the future, given the potential limitations of this study.

Prediction of the Intra-T Lymphocyte Tacrolimus Concentration after Kidney Transplantation with Population Pharmacokinetic Modeling.

The intracellular tacrolimus concentration in CD3+ T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods.

Effect of CYP3A5 Gene Polymorphisms on Tacrolimus Blood Concentrations and Adverse Events in Allogeneic Hematopoietic Stem Cell Transplant Patients

Effect of CYP3A5 Gene Polymorphisms on Tacrolimus Blood Concentrations and Adverse Events in Allogeneic Hematopoietic Stem Cell Transplant Patients