Tacrolimus Dose Research Articles

Studying the association between single nucleotide polymorphisms of metabolizing enzymes and the therapeutic serum levels of calcineurin inhibitors in Egyptian liver transplant patients

BackgroundMany clinical variables might impact the pharmacokinetics of calcineurin inhibitors (CIs). Different alleles of cytochromes P450 (CYP)3A4/5 and drug transporter P-glycoprotein are the main variables. Other variables include relocated type, treatment duration after transplantation, age, sex, dietary consumption, medications used and renal or hepatic impairment. Tacrolimus and cyclosporine are two main CIs extensively used in organ transplantation. Both drugs are metabolized by CYP3A4 and CYP3A5 isoforms, and single-nucleotide polymorphisms in these genes have been displayed to influence CIs pharmacokinetics. Another important gene is the pregnane X receptor (PXR), which manages the statement of a variety of genes including CYP3A4 genes. PXR has a clinical significance in CIs metabolism. The liver is the essential site for CIs metabolism. A decreased clearance with a prolonged CIs half-life was occurred in patients with impaired liver compared with patients with normal liver function. The presence of different genetic and clinical factors that may affect calcineurin inhibitors trough levels will consequently affect their immunosuppressant effect after liver transplantation.PurposeThis study aims to determine the effect of different genetic polymorphisms in CYP3A4 1B rs2740574 and PXR A7635G rs6785049 and other clinical factors that may affect calcineurin inhibitors pharmacokinetics after liver transplantation.ResultsThe presence of T allele in CYP3A4 gene was associated with elevated DATLs with P values of 0.00, 0.00, 0.007 and 0.00 after tacrolimus doses 4, 30, 60 and 90, respectively. Regarding PXR gene, the presence of G allele was associated with elevated DATLs in cyclosporine. About 432 correlations were tested in both drugs. In CYP3A4 genotype CC, male sex was associated with elevated DATLs interpreted by strong positive correlations and statistically significant difference in all DATLs, except DATL 60 (P value 0.374). No strong association was found between low hemoglobin levels and DATLs in almost all the follow-up periods. There were many positive relations between increased total and direct bilirubin and increased DATLs.ConclusionsStudying the various genetics and clinical factors that may affect calcineurin inhibitors serum concentrations is very essential for successful treatment plans after organ transplantation. These different factors may interact with each other and these complicated interactions may complicate the patient’s conditions post-transplantation. Considering all these complicated interactions is very crucial in monitoring treatment plans, especially in the presence of other comorbidities or chronic diseases. More studies with large number of patients should be conducted to explore more consequences of these interacting variables of treatment plans of these patients and all studied parameters in this study should be considered while monitoring patients after transplantation.

Long-term efficacy and safety of tacrolimus in anti-MuSK antibody-positive myasthenia gravis: a retrospective single-center cohort study.

To evaluate the long-term efficacy and safety of tacrolimus in patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG). We performed a retrospective, single-center, and cross-sectional study analyzing medical records of 18 MuSK-MG patients treated with tacrolimus for more than 1 year. The efficacy and safety of tacrolimus were evaluated by modified Osserman scale, Myasthenia Gravis Foundation of America post-intervention status, prednisone dosage, quantitative MG (QMG) scores, MG-activity of daily living (MG-ADL) scores, anti-MuSK antibody titers, blood routine, and serum biochemicals. After 4 weeks of tacrolimus treatment, there was a significant improvement in prednisone dose, QMG, and MG-ADL scores, which continued to improve over 1 year. In addition, clinical grade of modified Osserman scale was improved in all patients, 16 (88.9%) of whom were asymptomatic at the last visit. More importantly, the mean titers of anti-MuSK antibody were significantly decreased from 0.777 ± 0.381 to 0.283 ± 0.178 nmol/L after a median of 1.4 years of tacrolimus treatment in 9 patients with MuSK-MG (P = 0.015). All patients achieved minimal manifestations status (MMS) after tacrolimus treatment (range, 4-32 weeks). Subsequently, seven patients (38.9%) underwent a taper of tacrolimus dosage. However, four patients (57.1%) experienced an exacerbation. Adverse events occurred in 2 patients (11.1%), all of which were mild and resolved after the tacrolimus dose was adjusted or discontinued. Our results suggest that tacrolimus may be an effective and safe steroid-sparing treatment for patients with MuSK-MG. However, tacrolimus should be carefully tapered to avoid disease exacerbation.

Dosing strategy of tacrolimus when co-administered with Wuzhi tablet in renal transplant recipients.

Tacrolimus (TAC) is a first-line immunosuppressant to prevent allograft rejection. Wuzhi tablet is widely used as a TAC-sparing agent in China that could significantly elevate TAC exposure. However, insufficient data support the dose recommendation of TAC when co-administered with Wuzhi. A total of 305 adult renal transplant patients with 2,541 TAC trough concentrations (C0) were enrolled for population pharmacokinetic (PPK) modeling. CYP3A5 polymorphism was genotyped, and corresponding clinical factors were recorded. Nonlinear mixed-effects modeling and Monte Carlo simulation were used for dose recommendation. PK parameters were calculated based on one-compartment model with first-order absorption and elimination. The estimated total clearance (CL/F) and volume of distribution (Vd/F) of TAC were 23.84 L/h and 1,075.96 L, respectively. Wuzhi, CYP3A5 genotype, hematocrit (HCT), and weight were found to have a significant influence on CL/F. CL/F was significantly lower in the individuals who were CYP3A5 non-expressers and received TAC together with Wuzhi. CYP3A5 genotype (expressers or non-expressers), body weight (40-80 kg), and hematocrit (20 - 40%) were selected as the specific clinical scenarios, and the starting dose of TAC ranged from 1.5 to 4.5 mg when co-administered with Wuzhi. We establish a TAC PPK model comprising Wuzhi as a covariate in renal transplant recipients and recommend an initial dose of TAC when co-administered with Wuzhi, which could provide reference for the individualized regimens of TAC.

CYP3A4*1B but Not CYP3A5*3 as Determinant of Long-Term Tacrolimus Dose Requirements in Spanish Solid Organ Transplant Patients.

Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the CYP3A4*1B allele (0.101 mg/kg; p < 0.05). The results showed that patients with at least one CYP3A4*1B allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in CYP3A4*1B carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of CYP3A5*3 and CYP3A4*1B variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies.

Validation, implementation and quality control of a Torque Teno Virus qPCR in a multinational clinical trial

BackgroundImmunosuppressive medication after organ transplantation is usually dosed through therapeutic drug monitoring. Trough levels of antirejection medication however, do not adequately predict rejection or infections. The TTVguideIT trial is a multinational clinical trial evaluating the safety of Torque Teno Virus (TTV) load assessed by qPCR, as an alternative to trough level tacrolimus dosing. MethodsPrior to, and during the clinical trial, the inter-and intra-laboratory variability, accuracy, and precision of the TTV R-GENE® assay was evaluated through analysis of internal quality control (IQC), external quality assessment (EQA) and linearity panels performed by the thirteen participating clinical virology laboratories, each using their standard testing platforms. ResultsIQC samples with a target of 4 log10 copies/mL (cp/mL) were tested by the participating laboratories 130 times during the implementation phase and 987 times during the trial phase. They showed excellent accuracy, with an inter-laboratory standard deviation (SD) of 0.17 log10 cp/mL, and an intra-laboratory SD of 0.03 to 0.20 log10 cp/mL during the implementation phase, and an inter-laboratory SD of 0.19 log10 cp/mL, and an intra-laboratory SD 0.07 to 0.18 log10 cp/mL during the trial phase. Three EQA panels and three linearity panels showed similarly small variability during implementation as well as within the trial phase. ConclusionThis data shows that TTV load measurement can be standardized for use in a multinational clinical trial. By using IQC, LP and EQA samples, the quality and integrity of the assay can be compared between laboratories and precise and accurate results can be generated.

Risks of Tacrolimus and Paxlovid Therapy in SARS-CoV-2 Positive Transplant Recipients: A Case Discussion and Institutional Data Review

Abstract Introduction/Objective Transplant recipients maintained on immunosuppressants like tacrolimus continue to be at high risk for morbidity due to SARS-CoV-2 infection and are strong candidates for antiviral therapies. However, co- administration of the antiviral Paxlovid (nirmatrelvir/ritonavir) poses a significant risk to these patients due to ritonavir- mediated inhibition of CYP3A, an important mediator of tacrolimus metabolism. Consequently, Paxlovid therapy in post-organ transplant patients on tacrolimus requires careful consideration. Our investigation aims to assess the continuing risk posed by this drug-drug interaction and better understand clinical circumstances linked to critically high tacrolimus levels due to Paxlovid co-administration. Methods/Case Report We conducted a large-scale retrospective analysis of tacrolimus measurements at the University of Michigan Medicine beginning in January 2020. We also performed a detailed review of patients with critically high tacrolimus levels coinciding with Paxlovid administration. Results (if a Case Study enter NA) Of 39,752 tacrolimus measurements examined, 682 correspond to 329 patients with recent positive SARS-CoV-2 nucleic acid testing, and 37 correspond to 18 patients with documented Paxlovid co- administration. Patients receiving concurrent Paxlovid and tacrolimus demonstrate 1.6- and 1.8-fold higher mean tacrolimus levels (14.1 ng/mL, p = 3e-5) compared to other SARS-CoV-2 positive (8.7 ng/mL) and negative/untested (7.9 ng/mL) patients, respectively. Among SARS-CoV-2 patients, those prescribed Paxlovid are more likely to present with supratherapeutic tacrolimus levels (OR 4.1, 95% CI 1.6 – 10.7). A detailed case review of three organ transplant recipients presenting with tacrolimus levels &amp;gt;60 ng/mL and creatinine levels increased by 0.45 ± 0.27 mg/dL from baseline shows Paxlovid was prescribed at outside facilities, and regular tacrolimus dose was continued. Three other patients exhibited supratherapeutic tacrolimus levels (20 – 30 ng/mL), and creatinine levels increased by 0.41 ± 0.23 mg/dL from baseline despite dose reduction or cessation before initiating Paxlovid. Conclusion Our findings highlight the importance of communication between primary and tertiary care providers and caution when prescribing Paxlovid in populations managed with tacrolimus therapy.

Comparison of five tacrolimus measurement methods underscore the need for a standardized method to improve clinical outcomes

Abstract Tacrolimus is a widely used drug to prevent post-transplantation organ rejection by suppressing host immune response. While its efficacy is well established, tacrolimus is also known for narrow therapeutic index and debilitating adverse effects, rendering accurate measurement for therapeutic drug monitoring essential, to minimize drug toxicity and graft loss, and maximize organ rejection prevention. Tacrolimus can be quantitated by immunoassay (IA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, previous pairwise studies showed significant inter-assay variabilities between different IA methods, and between IA vs LC-MS/MS, which may be associated with the fact that IA measures parent drug and its metabolites, while LC-MS/MS measures only parent drug. No clear conclusion has been drawn about the optimal method. Transplant patients may also have their tacrolimus levels measured at different laboratories by different methods, causing inter-laboratory and intra-individual variabilities which may affect tacrolimus dose adjustment and monitoring and lead to adverse clinical outcomes. Here we performed a multi-platform comparison of tacrolimus quantification by two IA and 3 LC-MS/MS assays. A total of 216 specimens were analyzed for tacrolimus levels using chemiluminescence immunoassay (ChLIA, ARCHITECT, Abbott Diagnostic) and electrochemiluminescence immunoassay (ECLIA, Elecsys, Roche Diagnostic), and three LC-MS/MS assays (assigned names LC-MS/MS A (Agilent), Q (Waters), and W (Agilent)) in five different laboratories at four institutions. In one laboratory, the same analyses were performed on two different individual instruments (LC-MS/MS W1 and W2). Comparative results using LC-MS/MS A as reference were analyzed using Deming regression analysis, Pearson correlation, Bland Altman plots and bias calculation using GraphPad Prism version 10.1.1. While the correlations between each method with the LC-MS/MS A were good (r value: lowest 0.948 (LC-MS/MS Q), highest 0.988 (LC-MS/MS W2)), the ChLIA and ECLIA showed positive absolute bias of 2.1 and 1.2 ng/mL, respectively, and proportional bias of +26% and +17%, respectively. In comparison, the absolute bias of LC-MS/MS Q, W1 and W2 were -0.7, -0.02, and -0.1 ng/mL, respectively, with proportional bias of -11%, -0.2%, and -0.7%, respectively. The LC-MS/MS platforms showed tight agreement with one another, while IA methods were noticeably different, both from each other and from the LC-MS/MS, with a consistent positive bias, more pronounced with the ChLIA than the ECLIA. Here, our data-driven approach demonstrated that LC-MS/MS is superior to IA, and among IAs, ECLIA showed higher accuracy compared to ChLIA. However, inter-assay differences remain, emphasizing a need for tacrolimus assay standardization as well as prospective clinical trials to identify the most optimal method of tacrolimus measurement and improve patient outcomes.

Tacrolimus Dose Requirement in De Novo Adult Kidney Transplant Patients Treated With Adoport® Can Be Anticipated.

All the factors potentially influencing tacrolimus dose requirement and combinations thereof have never been thoroughly investigated, precluding accurate prediction of tacrolimus starting dose. This prospective, non-interventional, multicenter study in de novo adult kidney transplant recipients over the first year after transplantation aimed to investigate the factors influencing tacrolimus dose-standardized trough blood concentration (C0/D) over the first week post-transplant (D4-D7, primary objective), D8-M3 and M3-M12 (secondary objectives). Statistical analysis employed mixed linear models with repeated measures. Eighteen sites enrolled 440 patients and followed them up for 9.5 ± 4.1months. Age at baseline (p = 0.0144), end-stage renal disease (p = 0.0092), CYP3A phenotype (p < 0.0001), dyslipidemia at baseline (p = 0.0031), hematocrit (p = 0.0026), total bilirubin (p = 0.0261) and plasma creatinine (p = 0.0484) independently increased with log(C0/D) over D4-D7, explaining together 72.3% of the interindividual variability, and representing a robust model to estimate tacrolimus initial dose. Donor age and CYP3A phenotype were also influential over D8-M3 and M3-12, in addition to recipient age. Corticosteroids, diabetes at baseline, and ASAT yielded inconstant results between D8-M3 and M3-M12. We found no ethnicity effect when CYP3A phenotype was accounted for, and no food effect. Intra-individual variability over M3-M12 was moderate, and significantly lower in patients with chronic hepatic disorder (p = 0.0196) or cancer (p = 0.0132).

6984 New Onset Diabetes After Transplant: Need for Strict Glucose Monitoring

Abstract Disclosure: T. Chaudhary: None. O. Syed: None. M. Nawaz: None. R. Kaur: None. Introduction: Immunosuppressant use comes at a cost of challenging side effects, which are being discovered more as its use increases. One such example is our case of new-onset diabetes after transplant (NODAT).Patient presentation: A 36-year-old male with a past medical history of end-stage renal disease status post renal transplant (6/2023), hypertension, and hyperlipidemia who presented to the hospital in 10/2023 with fever, chills, and diarrhea. His vitals at that time were as follows: temperature 36.1C, blood pressure 148/84 mmHg, pulse 87 bpm, and a respiratory rate of 22. Lab work was significant for blood glucose 1144, anion gap 22, bicarbonate 13, potassium 7.3, Sodium 135, lipase 427, pH 7.3, urine ketones 80, HbA1C 11.5 %. CT scan of the abdomen revealed loss of peripancreatic fat and inflammatory changes surrounding the pancreas. His medication review included Tacrolimus 12 mg daily, Mycophenolate 500 mg BID, Valtrex 500mg daily, and fluconazole 200mg every other day. He was treated with 2 liters of normal saline bolus and started on maintenance fluid, and insulin drip as per DKA protocol. Calcium gluconate and an albuterol nebulizer were given for hyperkalemia. Tacrolimus and prednisone were held. Endocrinology and Nephrology were consulted. The patient was thought to have diabetes due to steroid use which were discontinued and the patient was discharged on subcutaneous insulin regimen and lower dose of tacrolimus. Despite discontinuation of steroids, patients continued to have raised glucose readings confirming the causative agent as tacrolimus. Conclusion: The current guidelines for post-kidney transplant patients recommend checking fasting blood glucose weekly for the first four weeks, then biweekly for two months, and then monthly thereafter. HbA1C should be checked every 3 months and if it is &amp;gt;6% then home glucose monitoring should be done as well. Although the frequency of these check-ups decreases, it is imperative for physicians to remember that patients can still develop NODAT months post-transplant. It is also essential to reinforce the importance of these glucose checks for the patient as missed diagnosis can lead to dangerous complications such as DKA. Presentation: 6/2/2024

Optimal tacrolimus levels for reducing CKD risk and the impact of intrapatient variability on CKD and ESRD development following liver transplantation.

This study aimed to identify the risk factors for chronic kidney disease (CKD) and end-stage renal disease (ESRD) following liver transplantation (LT), with a specific focus on tacrolimus levels and intrapatient variability (IPV). Among the 1,076 patients who underwent LT between 2000 and 2018, 952 were included in the analysis. The tacrolimus doses and levels were recorded every 3 months, and the IPV was calculated using the coefficient of variability. The cumulative incidence rates of CKD and ESRD were calculated based on baseline kidney function at the time of LT. The impact of tacrolimus levels and their IPV on the development of CKD and ESRD was evaluated, and the significant risk factors were identified. Within a median follow-up of 97.3 months, the 5-year cumulative incidence rates of CKD (0.58 vs. 0.24) and ESRD (0.07 vs. 0.01) were significantly higher in the acute kidney injury (AKI) group than in the normal glomerular filtration rate (GFR) group. In the normal GFR group, the tacrolimus levels were identified as a risk factor for CKD, with a level of ≤4.5 ng/mL suggested as optimal for minimizing the risk of CKD. Furthermore, the IPV of tacrolimus levels and doses emerged as a significant risk factor for CKD development in both groups (P<0.05), with tenofovir disoproxil fumarate also being a risk factor in HBV-infected patients. The IPV of tacrolimus levels was also a significant factor in ESRD development (P<0.05). This study elucidated the optimal tacrolimus through level and highlighted the impact of IPV on the CKD and ESRD development post-LT.

Early CYP3A5 Genotype-Based Adjustment of Tacrolimus Dosage Reduces Risk of De Novo Donor-Specific HLA Antibodies and Rejection among CYP3A5-Expressing Renal Transplant Patients.

Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome. 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years. CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups. Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers.

Getting Tacrolimus Dosing Right.

Tacrolimus (TAC) dosing is typically guided by the trough concentration (C0). Yet, significant relationships between TAC C0 and clinical outcomes have seldom been reported or only with adverse events. Large retrospective studies found a moderate correlation between TAC C0 and the area under the curve (AUC), where, for any given C0 value, the AUC varied 3- to 4-fold between patients (and vice versa). However, no randomized controlled trial evaluating the dose adjustment based on TAC AUC has been conducted yet. A few observational studies have shown that the AUC is associated with efficacy and, to a lesser extent, adverse effects. Other studies showed the feasibility of reaching predefined target ranges and reducing underexposure and overexposure. TAC AUC0-12 h is now most often assessed using Bayesian estimation, but machine learning is a promising approach. Microsampling devices are well accepted by patients and represent a valuable alternative to venous blood sample collection during hospital visits, especially when a limited sampling strategy is required. As AUC monitoring cannot be proposed very frequently, C0 monitoring has to be used in the interim, which has led to fluctuating doses in patients with an AUC/C0 ratio far from the population mean, because of different dose recommendations between the 2 biomarkers. We proposed estimating the individual AUC/C0 ratio and derived individual C0 targets to be used in between or as a replacement for AUC monitoring. Existing technology and evidence are now sufficient to propose AUC monitoring interspersed with individualized-C0 monitoring for all patients with kidney transplants while collecting real-world data to strengthen the evidence.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

Analytical modelling techniques for enhancing tacrolimus dosing in solid organ transplantation: a systematic review protocol.

Tacrolimus is an immunosuppressant commonly administered in transplant recipients. Given its narrow therapeutic range and susceptibility to various influencing variables, determining its optimal dosage is challenging. This systematic review seeks to identify effective analytical modelling techniques and methods for optimal tacrolimus dose prediction in solid transplant recipients. This review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The study will review the literature published from database inception to 11 March 2024, that assesses predictive models of tacrolimus dosing through analytical modelling techniques. We will include both randomised and non-randomised, as well as cross-sectional, qualitative and before-and-after studies and will perform our searches in four main databases-Ovid/MEDLINE, PubMed/MEDLINE, Scopus, Embase and Web of Science, and search engines including Centers for Disease Control (CDC) and Google Scholar. Papers that are not published in English or French are excluded from this study. A narrative synthesis and meta-analysis will be done if the extracted information permits such analysis. Conference abstracts will be ignored unless they are recent (published within 2 years of the search date). Ethics clearance is not required for this study as no primary data will be collected. The completed manuscript will be published, and the results of the study will be presented at conferences. International Prospective Register of Systematic Reviews (PROSPERO), CRD42024537212.

Sublingual Administration of Tacrolimus is Safe and Provides Similar Drug Exposure to Per-oral Route in Liver Transplant Recipients During Early Postoperative Period–A Large, Retrospective, Observational Study

BackgroundPer-oral(PO) administration of Tacrolimus(TAC) results in inadequate trough levels in early post-operative period in liver-transplant(LT) recipients who undergo Roux-en-Y hepaticojejunostomy for biliary reconstruction. Sublingual administration(SL) of tacrolimus provides an alternative route in such patients. ObjectiveTo assess feasibility and safety of SL tacrolimus in adult LT-recipients in early post-operative period and to compare therapeutic efficacy of SL administration of tacrolimus vs.PO route. Patients and MethodSingle-centre, retrospective, observational study carried out in adult living donor liver transplant(LDLT) recipients between January 2022 till December 2022. Recipients who underwent Roux-en-Y hepaticojejunostomy for biliary reconstruction, received tacrolimus through SL route till post-operative day(POD)5 as they were kept nil per oral constituted the study group while recipients who underwent duct-to-duct(D-D) anastomosis for biliary reconstruction were allowed orally from POD1 and received PO-tacrolimus were chosen as controls. Feasibility and safety of SL-Tacrolimus was assessed in terms of patient acceptance, need to discontinue SL-Tacrolimus, incidence of local adverse effects and systemic adverse events like neurotoxicity and nephrotoxicity. Therapeutic efficacy was evaluated by comparing median trough levels(TAC level) achieved and incidence of graft rejection between two groups. Results212 patients underwent LT during the study period of which 125 were included(58 in SL-group and 67 in PO-group). Both groups had comparable baseline characteristics. In SL-group, all patients tolerated SL-Tacrolimus well and no local adverse events were observed. Patients with SL-Tacrolimus administration achieved higher median TAC level(ng/ml) vs.PO route(5.85 vs 5(p=0.06)) despite similar median cumulative tacrolimus dose before assessing TAC-level. 50% patients achieved TAC level ≥6ng/ml in SL-group vs. 35.8% in PO-group(p=0.14). Incidence of neurotoxicity, nephrotoxicity and graft rejection during hospital stay were similar in both the groups(p=0.56,0.82 and 0.28 respectively). ConclusionSL-tacrolimus is safe and provides similar trough levels to PO-tacrolimus and may be considered as viable alternative whenever inadequate TAC-levels are anticipated through per-oral route.

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka

BackgroundImmunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans.MethodsSri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database.ResultsSLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7–65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7–37.9), 12.2% (10.4–13.9), 10.9% (9.2–12.6), 9.8% (8.2–11.4), 8.3% (6.8–9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7–3.4]), TPMT*3C (rs1142345) (1.9%[1.1–2.6]), TPMT*3B (rs1800460) (0.2%[0–0.5]), CYP3A5*6 (rs10264272) (0.2%[0–0.4]) and CYP3A4*18 (rs28371759) (0.1%[0–0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans.ConclusionSri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes. This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [Emax], Emax, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment. The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid Emax model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin. These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

Outcomes of COVID-19 in 24 hospitalized liver transplant recipients: an observational study

BackgroundAlthough liver transplant (LT) recipients are considered a population at risk of severe features of coronavirus disease 2019 (COVID-19), data in this regard are scarce and controversial. In this study, we reported the outcome of 24 cases of LT recipients who were hospitalized due to COVID-19 and investigated the role-playing factors in the severity of the disease.MethodsIn this single-center, analytic case-series study, eligible patients were among LT recipients who were hospitalized due to the diagnosis of COVID-19 based on positive results of polymerase chain reaction. Participants were categorized as severe COVID-19 if they were admitted to the intensive care unit, experienced respiratory failure demanding mechanical ventilation, or eventually died. Demographic and clinical data, COVID-19 symptoms and specific treatments, laboratory biomarkers, and immunosuppressive regimens and their alteration during the admission were recorded. Analysis was done using SPSS software.ResultsTwenty-four hospitalized LT patients were included, of which nine had severe and fifteen had non-severe COVID-19. Out of 9 patients with severe COVID-19, four sadly died. The analysis and comparison between the two groups revealed longer hospital stays (P = 0.02), lower lymphocyte counts (P = 0.002), and higher levels of C-reactive protein (CRP) (P = 0.006) in patients with severe COVID-19. Patients with non-severe COVID-19 had higher doses of tacrolimus and mycophenolate in their baseline immunosuppressive regimen (both P = 0.02).ConclusionLymphopenia and high CRP levels are associated with more severe forms of COVID-19 in LT patients. Mycophenolate may have protective properties against severe COVID-19. The role of severity indicators in LT patients with COVID-19 needs to be systematically recognized.

Model-Informed Precision Dosing of Tacrolimus: A Systematic Review of Population Pharmacokinetic Models and a Benchmark Study of Software Tools.

Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.