Therapeutic Drug Monitoring Of Tacrolimus Research Articles

Good correlation between tacrolimus concentrations using improved CMIA on the Alinity i analyzer and LC-MS/MS method from a reference laboratory but unexpected negative bias with another LC-MS/MS method from a different reference laboratory.

We compared tacrolimus concentrations obtained by the more recently US Food and Drug Administration-approved tacrolimus assay (CMIA) on the Alinity i analyzer (Abbott Laboratories) with a liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based method from 2 reference laboratories. We also investigated the correlation between the CMIA tacrolimus and Elecsys tacrolimus assays. Tacrolimus concentrations were measured in EDTA whole blood by the chemiluminescent microparticle immunoassay (CMIA) using the Alinity i analyzer, and then 2 aliquots were sent to 2 reference laboratories, both using ascomycin as the internal standard for the LC-MS/MS method. The total precision of the CMIA tacrolimus assay was excellent. When tacrolimus concentrations obtained by the LC-MS/MS method from reference laboratory A were plotted on the x-axis and corresponding CMIA values were plotted on the y-axis, the following regression equation was observed: y = 0.9721x + 1.005 (r = 0.95), indicating no significant bias with the CMIA. However, when tacrolimus values obtained from reference laboratory B were used for comparison, the regression equation was y = 0.7664x + 1.775 (r = 0.93), indicating significant negative bias with the CMIA. When we compared tacrolimus concentrations obtained by reference laboratories A and B, we observed positive bias with tacrolimus concentrations obtained by reference laboratory B. However, tacrolimus concentrations obtained by both CMIA and Elecsys immunoassays were comparable. Because of good correlation of tacrolimus concentrations using the CMIA and LC-MS/MS from reference laboratory A, our long-term reference laboratory for drug analysis, we concluded that the CMIA on the Alinity i can be used for therapeutic drug monitoring of tacrolimus.

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.

Improved LC-MS/MS method for the simultaneous quantification of tacrolimus and cyclosporine A in human blood and application to therapeutic drug monitoring.

In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC-MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy.

B-303 Comparison of Tacrolimus Concentrations Obtained By the Newly Approved Alinity i Tacrolimus Assay With a Reference Liquid-Chromatography Combined With Tandem Mass spectrometry Assay

Abstract Background Tacrolimus belongs to the calcineurin-inhibitor class of medications and used for preventing and maintenance of organ rejection in transplant recipients alone or in combination with other medications. Due to narrow therapeutic window and significant nephrotoxicity, this drug is routinely monitored with a suggested therapeutic range of 5–15 ng/mL. Recently, Abbott Laboratories (Abbott Park, IL) received FDA approval for using tacrolimus immunoassay on the Alinity i platform. We compared tacrolimus values in 101 transplant patients using Alinity i analyzer and a reference method based on liquid chromatography combined with mass tandem spectrometry (LC-MS/MS). Methods Tacrolimus immunoassay on the Alinity i analyzer is a chemiluminescent microparticle immunoassay (CMIA) requiring pretreatment of whole blood specimen prior to analysis. The analytical measurement range of the assay is 2–30 ng/mL. The left-over blood specimens were sent to Eurofins-Viracor reference laboratory in Lenexa, KS for analysis using LC-MS/MS method. After liquid-liquid extraction, specimens were analyzed using ascomycin as the internal standard for the presence of tacrolimus (assay is capable of analyzing other immunosuppressants simultaneously). UPLC C-18 column (waters) was used for separation using two mobile phases (A: 2.0 mM ammonium acetate in 0.1% formic caid in water and B: 2.0 mM ammonium acetate in 0.1% formic acid in methanol). Mass spectrometer was operated in positive ionization electrospray mode (tacrolimus m/z 821.6 &amp;gt; 768.6, ascomycin m/z 809.756.6. Results The total precision of the low control was 3.6% (mean: 4.48 ng/mL; CV 0.16 ng/mL, n = 20) while the total precision of the high control was 5.1% (mean: 25.4 ng/mL, SD: 1.29 ng/mL, n = 20). The linearity of the assay (2.0–30.0 ng/mL) was verified by running various calibrators as unknown. Comparing tacrolimus values in specimens from 101 transplant patients (49 kidney, 19 bone marrow transplant, 16 liver and 15 heart transplant) using the reference method (LC-MS/MS) as the x-axis and the corresponding values obtained by the tacrolimus immunoassay using Alinity I analyzer, we observed the following regression equation: y = 0.97 x + 1.005 (n = 101, r = 0.95). For kidney transplant recipients, the regression equation was y = 0.96 + 1.20 (n = 49, r = 0.94). Discussion Excellent correlation between tacrolimus values obtained by the newly FDA approved tacrolimus immunoassay with the reference LC-MS/MS based assay indicates further improvement in the performance of immunoassays for therapeutic drug monitoring of immunosuppressants. This may be due to reduced cross-reactivity of metabolites as indicated in the package insert. Conclusions The newly approved tacrolimus immunoassay for the application on the Alinity I analyzer can be used for routine therapeutic drug monitoring of tacrolimus in clinical laboratories.

Determining Plasma Tacrolimus Concentrations Using High-Performance LC-MS/MS in Renal Transplant Recipients.

Whole-blood therapeutic drug monitoring of tacrolimus is conducted to maintain tacrolimus concentrations within a safe and effective range. Changes in hematocrit cause variability in blood concentrations of tacrolimus because it is highly bound to erythrocytes. Measuring plasma concentrations may eliminate this variability; however, current methods have limitations owing to the use of cross-reactive immunoassays, plasma separation at nonbiological temperatures, and lack of clinical validation. This study aimed to develop and validate a clinically applicable method to measure plasma tacrolimus concentrations in renal transplant recipients and to examine the concentration differences between genotypic CYP3A5 expressors and nonexpressors. Plasma tacrolimus concentrations were measured in 9 stable renal transplant recipients who were genotypic CYP3A5 expressors or nonexpressors. Tacrolimus was extracted from plasma using solid-phase extraction, and liquid chromatography-tandem mass spectrometry was used for detection and quantitation. This assay was sensitive, selective, and linear between 100 and 5000 ng/L, with intraassay and interassay imprecision and inaccuracy <10% and <5% respectively. The extraction recovery of tacrolimus and ascomycin was 74%. Matrix ion suppression effects were 31.5% and 35% with overall recovery of 50.6% and 48.3% for tacrolimus and ascomycin, respectively. Whole-blood concentrations accounted for approximately 46% of the variation in plasma concentrations in CYP3A5 expressors and nonexpressors. No difference in dose-adjusted whole-blood and plasma concentrations was observed between CYP3A5 expressors and nonexpressors. This assay is clinically applicable with excellent performance and demonstrated that tacrolimus plasma concentrations highly correlated with whole-blood concentrations.

Area under the curve of tacrolimus using microsampling devices: towards precision medicine in solid organ transplantation?

Therapeutic drug monitoring of tacrolimus using trough concentration (Cmin) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, Cmin is just a proxy for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and Cmin in patients benefiting from a complete pharmacokinetic profile using a microsampling approach. Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with Cmin was then explored. In parallel, we estimated AUC using the sole Cmin and regression equations according to the post-transplantation days and the galenic form. Weak correlations were found between 24-h AUC observed and the corresponding Cmin (R2 = 0.60) and between AUC observed and expected using the sole Cmin (R2 = 0.62). Therapeutic drug monitoring of tacrolimus using Cmin leads to over- or under-estimate drug exposure in 40.3% of patients. Tacrolimus Cmin appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.

Therapeutic Drug Monitoring of Tacrolimus in Tunisian Renal Transplant Patients during the Tuberculosis Infection: A Retrospective, Observational, Single-centre Analysis.

A retrospective, observational, single-center analysis was performed at the Department of Clinical Pharmacology (National Centre of Pharmacovigilance, Tunisia). We analyzed the database of patients who received TAC from 2009 until 2018. We included samples provided from renal transplant patients infected by Mycobacterium tuberculosis after transplantation. Trough blood levels (C0) were determined using an immunoassay analyzer. The Therapeutic Range (TR) of TAC was considered between 5 and 10 ng/mL. Pharmacokinetic parameters were compared between the period of co-administration of TAC/ATT (period A) and the period during which patients received only TAC (period B). Seven renal transplant patients treated by TAC were included. 41 samples were analyzed (16; period A, 25; period B). Only 6 % of C0 values were found within TR during period A, while this rate was 44% during period B. During period A, 88% of TAC C0 was under the lower limit of TR, indicating a high risk of transplant rejection. The mean C0 and C0/D were significantly lower during period A (3.11±1.53 ng/mL vs 7.11 ± 3.37 ng/mL; p = 0.001 and 33.06 ± 24.89 vs 83.14 ± 44.46; p = 0.0006, respectively), without difference in doses between periods. Considering the results of this study, clinicians are suggested to monitor TAC closely in this particular circumstance.

Investigation of Therapeutic Drug Monitoring of Tacrolimus in Different Age Groups: Results from a Turkish Nationwide Study

Background: The blood level of tacrolimus (TAC) used for post-transplant immunosuppression should be within the therapeutic index. Geriatric individuals may be at risk of organ rejection because, in this age group, routine drug use is usually disrupted, and the bioavailability of aging-related drugs is decreased. Objective: The aim of this study was to analyze the age-related variability of blood TAC levels in patients in Turkey. Methods: In this study, 697,616 patients who underwent TAC measurement in the laboratories of public, private, and university hospitals between 2018 and 2020 were identified from the Health-net database of the Ministry of Health. The results of patients aged ≥65 years were compared with those of patients aged &lt;65 years. The differences between the sexes in the same age group were also examined. Data from the Turkish Ministry of Health National Electronic Database were used to design a multicenter retrospective cohort study. Results: The study included 697,616 patients. The mean TAC concentration was 7.2 ± 6.25 ng/mL for all the patients, 7.13 ± 6.7 ng/mL for the female patients, and 7.24 ± 5.96 ng/mL for the male patients. A statistically significant difference in TAC concentration was found between men and women in the general population. Groups aged ≥65 years were compared among themselves. A statistically significant decrease in TAC concentration was found only in the age group of 75–79 years (5.63 ± 4.09 ng/mL) of women compared with the men. In all other age groups, the TAC levels of the men were lower. Conclusions: The proportion of patients with TAC concentrations lower than the therapeutic index was higher in the groups aged ≥65 years. Thus, patients aged ≥65 years may be at risk of organ rejection, as optimum immunosuppression cannot be achieved. In these patients, more frequent drug monitoring and providing training to ensure the compliance of the patient and the patient's relatives in the use of TAC may be recommended.

Switch from a ritonavir to a cobicistat containing antiretroviral regimen and impact on tacrolimus levels in a kidney transplant recipient

BackgroundSolid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug–drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat.Case presentationHere we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties.ConclusionsThis case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.

New perspectives for the therapeutic drug monitoring of tacrolimus: Quantification in volumetric DBS based on an automated extraction and LC-MS/MS analysis

Volumetric microsampling devices have been developed for home-based capillary blood sampling and are now increasingly proposed for the therapeutic drug monitoring (TDM) of immunosuppressive drugs. Our objective was to validate a LC-MS/MS method for tacrolimus quantification based on both a manual and an automated extraction of dried blood spots (DBS) collected with a volumetric microsampling device.DBS collection was performed by placing a drop of whole blood (WB) pre-spiked with tacrolimus onto a sealing film and placing the hemaPEN® device (Trajan Scientific and Medical, Melbourne, Australia) into the drop according to the device specifications. Tacrolimus was quantified using a fully automatic preparation module connected to a LCMS system (CLAM-3020® and LCMS-8060®, Shimadzu, Marne-la-Vallée, France). The method was validated analytically and clinically in accordance with the EMA and IATDMCT guidelines.The method was linear from 1 to 100 µg/L. Within- and between-run accuracy and precision fulfilled the validation criteria (biases and imprecision <15% or 20% for the lower limit of quantification). No hematocrit effect, matrix effect or carry-over was observed. No selectivity issue was identified and dilution integrity was confirmed. Tacrolimus in DBS was stable for 14 days at room temperature and +4°C, and for 72h at +60°C. There was a good correlation between tacrolimus concentrations measured in WB and in DBS of 20 kidney and liver transplant recipients (r=0.93 and 0.87, for manual and automated extraction respectively).A method for tacrolimus measurement in DBS collected with volumetric micro-sampling device, based on a fully automated process from pre-treatment to LC-MS/MS analysis was developed and validated according to analytical and clinical criteria. This performing sampling and analytical procedure opens the perspective of an easier, faster and more efficient TDM of tacrolimus for patients, clinicians and laboratories.

Pharmacokinetic Model Based on Stochastic Simulation and Estimation for Therapeutic Drug Monitoring of Tacrolimus in Korean Adult Transplant Recipients: Erratum.

Pharmacokinetic Model Based on Stochastic Simulation and Estimation for Therapeutic Drug Monitoring of Tacrolimus in Korean Adult Transplant Recipients: Erratum.

Use of tecovirimat for mpox infection followed by JYNNEOS vaccination postinfection in a liver transplant recipient.

Use of tecovirimat for mpox infection followed by JYNNEOS vaccination postinfection in a liver transplant recipient.

Fingerprick Microsampling Methods Can Replace Venepuncture for Simultaneous Therapeutic Drug Monitoring of Tacrolimus, Mycophenolic Acid, and Prednisolone Concentrations in Adult Kidney Transplant Patients.

Kidney transplant patients undergo repeated and frequent venepunctures during allograft management. Microsampling methods that use a fingerprick draw of capillary blood, such as dried blood spots (DBS) and volumetric absorptive microsamplers (VAMS), have the potential to reduce the burden and volume of blood loss with venepuncture. This study aimed to examine microsampling approaches for the simultaneous measurement of tacrolimus, mycophenolic acid, mycophenolic acid glucuronide (MPAG), and prednisolone drug concentrations compared with standard venepuncture in adult kidney transplant patients. DBS and VAMS were simultaneously collected with venepuncture samples from 40 adult kidney transplant patients immediately before and 2 hours after immunosuppressant dosing. Method comparison was performed using Passing-Bablok regression, and bias was assessed using Bland-Altman analysis. Drug concentrations measured through microsampling and venepuncture were also compared by estimating the median prediction error (MPE) and median absolute percentage prediction error (MAPE). Passing-Bablok regression showed a systematic difference between tacrolimus DBS and venepuncture [slope of 1.06 (1.01-1.13)] and between tacrolimus VAMS and venepuncture [slope of 1.08 (1.03-1.13)]. Tacrolimus values were adjusted for this difference, and the corrected values showed no systematic differences. Moreover, no systematic differences were observed when comparing DBS or VAMS with venepuncture for mycophenolic acid and prednisolone. Tacrolimus (corrected), mycophenolic acid, and prednisolone microsampling values met the MPE and MAPE predefined acceptability limits of <15% when compared with the corresponding venepuncture values. DBS and VAMS, collected in a controlled environment, simultaneously measured multiple immunosuppressants. This study demonstrates that accurate results of multiple immunosuppressant concentrations can be generated through the microsampling approach, with a preference for VAMS over DBS.

Therapeutic Drug Monitoring of Tacrolimus Based on Volumetric Absorptive Microsampling Technique (VAMS) in Renal Transplant Pediatric Recipients-LC-MS/MS Method Development, Hematocrit Effect Evaluation, and Clinical Application.

Tacrolimus (TAC) is post-transplant pharmacotherapy's most widely used immunosuppressant. In routine clinical practice, frequent uncomfortable venipuncture is necessary for whole-blood (WB) collection to check trough TAC levels. Volumetric absorptive microsampling (VAMS) is an alternative strategy to WB collection. In this study, we aimed to validate and develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for TAC quantification in WB and VAMS samples. After extraction with water and protein precipitation, the samples were directly analyzed using LC-MS/MS. Whole-blood and VAMS capillary-blood samples were collected from 50 patients treated with TAC during the follow-up visits. The cross-correlation between the developed methods was evaluated using Passing-Bablok regression and a Bland-Altman bias plot. The matrix effect (ME) and carry-over were insignificant for both scenarios. There was a high correlation between the processes and no significant clinical deviation. LC-MS/MS methods were successfully developed and validated in the 0.5-60 ng/mL calibration range. This study demonstrated and confirmed the utility of VAMS-based TAC monitoring in the pediatric population. This is the first study to directly develop and validate the VAMS LC-MS/MS method for evaluating the hematocrit effect in the pediatric population. The statistical correlation between immunochemical and VAMS-based methods was satisfactory.

Pharmacokinetic Model Based on Stochastic Simulation and Estimation for Therapeutic Drug Monitoring of Tacrolimus in Korean Adult Transplant Recipients.

Tacrolimus shows high variability in inter- and intraindividual pharmacokinetics (PK); therefore, it is important to develop an appropriate model for accurate therapeutic drug monitoring (TDM) procedures. This study aimed to develop a pharmacokinetic model for tacrolimus that can be used for TDM procedures in Korean adult transplant recipients by integrating published models with acquired real-world TDM data and evaluating clinically meaningful covariates. Clinical data of 1829 trough blood samples from 269 subjects were merged with simulated data sets from published models and analyzed using a nonlinear mixed-effect model. The stochastic simulation and estimation (SSE) method was used to obtain the final parameter estimates. The final estimated values for apparent clearance, the volume of distribution, and absorption rate were 21.2 L/h, 510 L, and 3.1/h, respectively. The number of postoperative days, age, body weight, and type of transplant organs were the major clinical factors affecting tacrolimus PK. A tacrolimus PK model that can incorporate published PK models and newly collected data from the Korean population was developed using the SSE method. Despite the limitations in model development owing to the nature of TDM data, the SSE method was useful in retrieving complete information from the TDM data by integrating published PK models while maintaining the variability of the model.

Evaluation of a Standardized Tacrolimus Therapeutic Drug Monitoring Protocol in Stable Kidney Transplant Recipients.

Introduction: Transplant nurse coordinators have assisted in accurately adjusting tacrolimus doses under a collaborative practice agreement for kidney transplant recipients in the early post-operative period. This study evaluated the efficiency of a standardized tacrolimus therapeutic drug monitoring (TDM) protocol in stable outpatient recipients. Design: We conducted a single-center, retrospective study of adult patients who received a kidney transplant at least 3 years ago and were taking immediate-release tacrolimus. Before September 2019, transplant coordinators consulted transplant providers for management of all tacrolimus trough levels (Pre-Arm). Under the standardized protocol, coordinators directly responded to out-of-range tacrolimus trough levels (Post-Arm). The primary outcome was the time to intervention for out-of-range levels. Secondary outcomes included adverse events, time in therapeutic range, coefficient of variation (CV), and protocol compliance. Results: Of 1712 levels (from 174 patients), 259 levels (15.1%) were out-of-range. The overall time to intervention was 13.2 hours shorter (95% CI: -26.4 to -0.1 hours; P = 0.048) in the Post-Arm. There was no rejection, graft loss, or death during the study period. The time in therapeutic range was 89.3% (17.6%) vs 89% (19.4%; P = 0.816) and CV was 19.7% (15.8%) vs 18.4 (10.7%; P = 0.358) in the Pre-Arm and Post-Arm, respectively. Within the Post-Arm, the protocol required coordinators to independently intervene on 96 out-of-range levels (65.8%), which were accurately addressed 57.5% of the time. Conclusion: Implementation of a standardized TDM protocol improved efficiency without compromising major clinical outcomes or intrapatient variability (IPV) of tacrolimus levels for stable kidney recipients in the outpatient setting.

A Prediction Model for Tacrolimus Daily Dose in Kidney Transplant Recipients With Machine Learning and Deep Learning Techniques.

Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.

Effects of Voriconazole Exposure on the Pharmacokinetics of Tacrolimus in Lung Transplantation Patients, Based on Therapeutic Drug Monitoring Data

Tacrolimus and voriconazole are usually used simultaneously in lung transplantations. Voriconazole can increase tacrolimus concentrations by inhibiting the cytochromeP450 (CYP) enzyme, which poses a great challenge for dose adjustment. The aim of this study is to clarify the correlation between voriconazole exposure and tacrolimus trough concentrations (C0 ), and to establish a population pharmacokinetic model including voriconazole trough concentrations (VOZ) as a covariate for dose optimization. All data were retrospectively collected from lung transplantation patients who were subjected to therapeutic drug monitoring of tacrolimus and voriconazole. The correlation between C0 and VOZ or voriconazole daily doses was analyzed by Spearman's correlation. A total of 52 patients accounting for 351 pairs of tacrolimus and voriconazole trough concentrations were included. C0 and C0 /daily dose of tacrolimus (DD) had a significant correlation with VOZ (P<.01) rather than voriconazole daily doses. A linear one-compartment model with first-order absorption and elimination was used as the basic model for population pharmacokinetic analysis. Body weight (WT), DD, VOZ, and hematocrit (HCT) were included as covariates in the final model. With the increase in voriconazole concentrations, the apparent total clearance (clearance/bioavailability, CL/F) of tacrolimus decreased significantly. The simulation results showed that the highest proportion of C0 within the target range can only reach <50% when the optimal initial drug regimen was given. Therefore, both tacrolimus and voriconazole concentrations need to be continuously monitored during treatments in lung transplantation patients, and the tacrolimus dose can be optimized according to VOZ based on the established pharmacokinetic model.

MO999: Intra-Patient Variability of Tacrolimus in Kidney Transplant Patients: An Experience of a Kidney Disease Specialist Hospital

Abstract BACKGROUND AND AIMS The complexity of tacrolimus pharmacokinetics results in a unique tacrolimus recommendation in transplant centers and global level [1]. Intra-patient variability (IPV) of tacrolimus has become a simple and interesting marker to predict transplant outcomes in addition to minimum concentration (Cmin) monitoring [2–4]. As differences in ethnic affecting tacrolimus pharmacokinetics and patient response, we investigated a pilot study of tacrolimus IPV in our institution. METHOD The cohort study was conducted in all new kidney transplant patients receiving twice-daily tacrolimus as a standard immunosuppressive therapy. Patients were switched from twice-daily tacrolimus to other immunosuppressive agents were excluded from the study. All patients were followed-up at an outpatient clinic with routine monitoring. A one-year follow-up period was evaluated in the study. The primary outcome was the IPV of tacrolimus during the 3–12 months after transplantation. IPV of tacrolimus Cmin was calculated by [SD/(mean tacrolimus dose-normalized Cmin)] × 100.5 We categorized the IPV of tacrolimus into three levels: low (0%–10%), intermediate (11%–30%) and high IPV (&amp;gt;30%). The secondary outcomes were to assess renal function by eGFR and pre-defined factors associated with the IPV of tacrolimus. The study protocol was reviewed and approved by the Thai Clinical Trial Registry (TCTR20210519005). RESULTS There were 56 patients who underwent kidney transplantation during the study period. Of these 56 patients, 12 patients experienced late conversion from twice-daily to once-daily tacrolimus or were combined with sirolimus, and 4 patients became lost to follow-up. A total of 40 patients completed the one-year study period and were included in the analysis. The mean age of patients was 50.85 ± 11.07 years. A total of 39 patients received basiliximab, and one patient received anti-thymoglobulin as an induction therapy. Baseline characteristics are shown in Table 1. At 3–12 months after transplantation, the mean IPV of tacrolimus was 23.77% ± 11.23%. When categorized patients according to %IPV of tacrolimus, we found that most patients were in the intermediate IPV. The percentage of patients in each category was 7.5%, 65% and 27.5% of patients in low, intermediate and high IPV of tacrolimus, respectively (Fig. 1). The eGFR at discharge of patients with high IPV was significantly lower than that with low to intermediate IPV (P = .0282). For pre-defined factors associated with IPV of tacrolimus, the hemoglobin level at 3 months of patients with high IPV (11.23 ± 1.72 g/dL) was significantly lower than that of patients with low to intermediate IPV (12.54 ± 1.77, P = .0425). All patients were compliant as measured by pill counts and no difference in drug interaction between groups. Renal function remained stable and was similar between groups at one year of follow-up (52.03 ± 14.74 and 57.93 ± 16.40 mL/min/1.73 m2P = .3254 for high IPV and low to intermediate IPV, respectively). CONCLUSION Our findings showed that most patients were in low to intermediate IPV of tacrolimus. A low level of eGFR at discharge and a low level of hemoglobin in the early-post transplant period were associated with high IPV of tacrolimus. Therefore, clinicians should be cautious to monitor levels and adjust the dose of tacrolimus, especially if patients at risk of tacrolimus variability. A practical calculation of IPV provides a tremendous benefit for clinicians to individualized tacrolimus therapeutic drug monitoring. This study was a starting point and would expand for our large patient population. Clinical correlation with IPV of tacrolimus and IPV-directed interventions for Asian population are needed to improve tacrolimus using for achieving transplant outcomes.

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study.

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown. Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5–10 ng/ml. Results: We found that 32 and 68% of samples were respectively collected early (2–180 min) and delayed (4–315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5–1, 1–2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml. Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.