Tacrolimus Dose Requirements Research Articles

Potential Influence of Interleukin-6 -174G/C Gene Polymorphism on Kidney Graft Function and Tacrolimus Dose Requirements: Five-Year Follow-up

1.Introduction: The study aimed to investigate the influence of interleukin (IL)-6 -174G/C gene polymorphism on graft function (defined as estimated glomerular filtration rate, eGFR), as well as on the tacrolimus (Tac) pharmacokinetics during the five years after kidney transplantation. 2.Methods: The study included 115 Caucasian kidney transplant recipients on Tac-based immunosuppression. The patients were followed between 6 and 60 post-transplantation months. Interleukin-6 and CYP3A5 genotyping were performed. 3.Results: Patients carrying the IL-6 -174GG genotype had lower eGFR values compared to the patients with the IL-6 -174GC and -174CC genotypes at the 12th, 48th and 60th post-transplantation months. The linear regression analysis indicated that eGFR at the 6th post-transplantation month and IL-6 -174G/C polymorphism are independent predictors of eGFR values in the late post-transplantation period. The IL-6 -174GG genotype carriers had lower dose-adjusted trough concentration (C0/D) of Tac compared to the IL-6 C allele carriers during the entire observation period (except at the 24th month), while this effect was independent of the CYP3A5 genotype within three years post-transplantation. 4.Conclusion: Interleukin-6 genotyping could be an additional tool to categorize patients toward the risk of graft deterioration in the long-term post-transplantation period. The IL-6 genotyping could be supportive in genotype-guided dosing 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.

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).

Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation

Kidney transplantation stands as the ultimate recourse for restoring vital organ functions, particularly in cases of end-stage kidney disease where alternative treatments, such as dialysis, prove less effective. With over 102,000 kidney transplants conducted globally in 2022, the demand for organ transplantation is ever-increasing, fueled by a rising incidence of end-stage renal disease attributed to causes like diabetes and hypertension.&lt;br /&gt; Despite significant advancements in kidney transplantation, immunosuppressive therapy remains crucial to preventing graft rejection. Tacrolimus (TAC), a calcineurin inhibitor, plays a pivotal role in this regard. Discovered in 1984, TAC inhibits T-lymphocyte activation, preventing acute rejection by disrupting the transcription of crucial genes involved in early T-cell activation. However, the use of TAC is not without challenges. The drug exhibits serious side effects, a narrow therapeutic index, and unpredictable pharmacokinetics. Therapeutic drug monitoring (TDM) becomes imperative in daily practice to maintain TAC blood concentrations within the therapeutic range. This literature review delves into the genetic aspects influencing TAC metabolism, focusing on key polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes. Genetic variations in CYP3A5, a major enzyme in TAC metabolism, impact enzyme activity, necessitating personalized dosing strategies. CYP3A4 polymorphisms, especially CYP3A4*22, demonstrate associations with altered TAC clearance and dose requirements. The ABCB1 gene, encoding P-glycoprotein, another player in TAC pharmacokinetics, also exhibits polymorphisms influencing drug absorption and distribution. The ABCB1 3435C&amp;gt;T variant, in particular, shows potential implications on Tacrolimus bioavailability. Understanding these genetic variations aids in the development of personalized dosing regimens. Studies suggest that tailoring TAC doses based on CYP3A5 genotypes significantly improves the proportion of patients achieving therapeutic concentrations. Additionally, incorporating genetic information, particularly CYP3A4*22, into dosing strategies enhances the precision of TAC therapy, reducing the risk of adverse effects.

Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients.

In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis.

Introduction: IL-6 and IL-10 may affect the activity of cytochrome P450 (CYP) 3A enzymes involved in tacrolimus (Tac) metabolism. Moreover, the effect of IL-6 and IL-10 on Tac pharmacokinetics may differ with respect to the genetic variations in their genes.Aim: To examine the influence of IL-6 and IL-10 gene polymorphisms on Tac dose requirements and exposure over a 5-year period following kidney transplantation. Univariate and standard multivariate linear regression and Monte Carlo analysis were performed to investigate potential covariates influencing Tac dose-adjusted trough concentration (C0/D) in various post-transplantation periods.Materials & methods: IL-6 (-174G>C), IL-10 (-1082G>A, -819C>T and -592C>A) genotype, Tac daily dose, C0, C0/D and intrapatient variability data were collected from 113 patients.Results: Multivariate regression analysis and accompanied Monte Carlo simulation underscore the importance of considering IL-6 -174G>C and IL-10 -1082G>A gene polymorphisms, alongside Tac metabolic phenotype and post-transplantation period, when tailoring Tac dosage regimen.Conclusion: This study provides valuable insights regarding the individualized adjustment of Tac treatment in various post-transplantation periods.

Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2%vs. 9.5%, p=.03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3%vs 7.7%, p=.56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.

A longitudinal study of long-term renal outcome after pediatric liver transplantation in relation to CNI exposure.

Chronic kidney disease (CKD) is reported in 20%-30% of children after liver transplantation (LT). One of the proposed underlying causes is the long-term exposure to tacrolimus, a calcineurin inhibitor (CNI), which is the main immunosuppressive drug used after LT. Variation in tacrolimus absolute exposure and relative dose requirements are believed to be important risk factors for developing CNI-associated nephrotoxicity. To describe the long-term renal outcome of pediatric LT recipients and determine the effects of tacrolimus exposure on renal outcome parameters. Retrospective single center study of renal function (GFR, proteinuria) and pharmacokinetic parameters (C0 , AUC0-12h ) obtained during annual follow-up in children after liver transplantation, between 1998 and 2019. Relevant pharmacogenetic variants for tacrolimus disposition (CYP3A5 and ABCB1) were determined in recipients and donors. The evolution of individual renal function and tacrolimus exposure was evaluated using linear mixed models for repeated measurements. Twenty-six children were included (mean follow-up: 10.4 years (range 2-18.9)). Mean estimated GFR was 109.3 (SE: 7.4), vs. measured: 91.3 mL/min/1.73 m2 (SE: 6.3), which remained stable during follow-up. CKD stage ≥2 was observed in 32.8% of the visits based on eGFR versus 50.0% on mGFR. CKD stage ≥3 was uncommon (4.1% and 6.2% resp.). Mean tacrolimus C0 was 5.3 ng/mL (SE: 2.5) with a AUC0-12h of 72.7 ng*h/mL (SE: 30.3), which demonstrated a small decrease during follow-up. There was a negative correlation between C0 and mGFR (rS = -0.3; p < .001). We found no correlation between GFR and tacrolimus dose requirements ((ng/mL)/(mg/kg)) or pharmacogenetic background. Renal function during long-term follow-up after pediatric LT remained stable for the majority of our cohort. However, mild CKD was relatively common, warranting follow-up into adulthood. Although absolute tacrolimus exposure has a small depressing effect on concurrent GFR, there is no progressive deterioration of GFR due to long-term exposure, dose requirements or genetic background under the current target levels. These findings should be confirmed in a larger sample set, ideally including data from multiple centers.

Effect of CYP3A4*22, CYP3A5*3 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients.

This study aimed to investigate the combined effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements. One hundred thirty renal transplant patients placed on either tacrolimus or cyclosporine were recruited, where the effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on their dose requirements were studied at days 14, 30, and 90 post-transplantations. The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was significantly lower in the fast metabolizers group ( CYP3A5*1/POR*28(CT/TT ) carriers) than in the poor metabolizers group ( CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) ( P = 0.001, <0.001, and 0.003, respectively). Meanwhile, there was no significant effect of this gene combination on cyclosporine C0/D. Combining the CYP3A5*3, POR*28 , and CYP3A4*22 genotypes can have a significant effect on early tacrolimus dose requirements determination and adjustments. However, it does not have such influence on cyclosporine dose requirements.

Study of the Effect of ABCB1 Single Nucleotide Polymorphism on Tacrolimus Dose Requirements in Liver Transplant Patients

Abstract Background Liver transplantation (LT) is the only effective radical cure for all types of end stage liver diseases. Major advances have been made in the field of liver transplantation due to improvements in surgical techniques and organ conservation as well as optimization of intensive care and immunosuppressive management. Aim of the Work The aim of the present work is to assess the influence of ABCB1 gene polymorphism of liver transplant recipients on blood level and dose requirements of oral tacrolimus, in an attempt to help in designing an individualized tacrolimus regimen for Egyptian liver transplant recipient. Patients and Methods The study included 25 liver transplant recipients and their respective donors. All subjects of this study were subjected to full medical history, Clinical evaluation, Laboratory investigations, and ABCB1 gene polymorphism evaluation by RT-PCR. Tacrolimus trough level was evaluated for all the recipients during the first 3 months post transplantation. Results The present study revealed that the presence of CC genotype was significantly correlated to the effect on tacrolimus C/D ratio and Weight adjusted tacrolimus dose during the first week of the first and 2nd month (Z = -2.108, P &amp;lt; 0.05) but not the 3rd month post transplantation (p-value &amp;gt;0.05). Subjects carrying CC genotype required higher doses of tacrolimus to achieve the desired trough levels compared to subjects carrying CT and TT genotypes. The same effect was observed over the whole period of the study but the results were statistically non-significant (p-value&amp;gt;0.05). Recipients who received liver tissue from donors carrying CC genotype also required higher doses of tacrolimus and reached lower levels of blood tacrolimus trough levels. Conclusion The present study revealed that ABCB1 CC genotype of both recipients and donors of liver transplantation was significantly associated with increased required tacrolimus dose early after liver transplantation reaching statistically significant level in the first week of the first and second months.

#3185 INFLUENCE OF COMBINED CYP 3A4/5 AND POR*28 GENETIC POLYMORPHISMS ON TACROLIMUS AND CCLOSPORINE DOSE REQUIREMENTS IN INCIDENT RENAL TRANSPLANT PATIENTS

Abstract Background and Aims Calcineurin inhibitors, cyclosporine and tacrolimus have a narrow therapeutic index and have wide intra- and inter individual pharmacokinetic variability. They are metabolized mainly by CYP3A4 and CYP3A5. The P450 oxidoreductase POR*28 variant allele has been associated with changes in cytochrome P450 enzymatic activity that can affect the therapeutic level of both medications. The aim of this study is to investigate the allelic frequency of the POR*28 in Egyptian renal transplant patients and to evaluate the effect of the presence of CYP3A5*1, CYP3A4*22, and POR*28 genetic polymorphism on calcineurins inhibitos dose requirements and adjustments. Method A prospective clinical trial that included 130 renal transplant patients placed on either tacrolimus or cyclosporine. Patients were genotyped for POR*28, CYP3A4*22, and CYP3A5*1. The relation between the present genetic polymorphisms and tacrolimus and cyclosporine doses and dose adjustments were studied at days 14, 30, and 90 post-transplantation. Results The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was highly statistically significant in the fast metabolizers group (CYP3A5*1/POR*28T carriers) than in the slow metabolizers group (CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) (p value 0.001, &amp;lt;0.001, and 0.003, respectively). There was no significant effect for this gene combination on cyclosporine (C0/D). Conclusion Combining the CYP3A5*1, POR*28, and CYP3A4*22 genotypes can be of significant value in early tacrolimus dose requirements and adjustments. However, it does not have any influence on cyclosporine dose requirements.

(1159) Sirolimus and Tacrolimus Dosing Requirements in Pediatric Heart Transplant Recipients to Target Combined Trough Levels

(1159) Sirolimus and Tacrolimus Dosing Requirements in Pediatric Heart Transplant Recipients to Target Combined Trough Levels

Predictive Capacity of Population Pharmacokinetic Models for the Tacrolimus Dose Requirements of Pediatric Solid Organ Transplant Recipients.

Transplant recipients require individualized tacrolimus doses to maximize graft survival. Multiple pediatric tacrolimus population pharmacokinetic (PopPK) models incorporating CYP3A5 genotype and other covariates have been developed. Identifying the optimal popPK model is necessary for clinical implementation in pediatric solid organ transplant. The primary objective was to compare the dose prediction capabilities of the developed models in pediatric kidney and heart transplant recipients. Pediatric kidney or heart transplant recipients treated with tacrolimus and available CYP3A5 genotype data were identified. The initial weight-based tacrolimus dose and first therapeutic tacrolimus dose were collected retrospectively. Three published popPK models were used to predict the tacrolimus dose required to achieve a tacrolimus trough concentration of 10 ng/mL. Model dose predictions were compared with the initial and first therapeutic doses using Friedman test. The first therapeutic dose was plotted against the model-predicted dose. The median initial dose approximately 2-fold lower than the first therapeutic dose for CYP3A5 expressers. The Chen et al model provided the closest estimates to the first therapeutic dose for kidney transplant recipients; however, all 3 models tended to underpredict the observed therapeutic dose. For heart transplant recipients, Andrews et al model predicted doses that were higher than the initial dose but similar to the actual therapeutic dose. Weight-based tacrolimus dosing appears to underestimate the tacrolimus dose requirements. The development of a separate popPK model is necessary for heart transplant recipients. A genotype-guided strategy based on the Chen et al model provided the best estimates for doses in kidney transplant recipients and should be prospectively evaluated.

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers.

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1vs. 8.1, p=.015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.

Therapeutic challenges of tacrolimus dose requirement and trough level in an indian pediatric renal transplant recipient with extensive metabolizer (Cytochrome P450 3A5*1)

Pediatric patients need a higher dose of tacrolimus for posttransplant immunosuppression due to its high clearance. In addition, genetic polymorphism in cytochrome P450 (CYP) 3A5 enzyme (CYP3A5*1/*3) is an important determinant for its serum concentration. Substantial data exist about the requirement of higher doses of tacrolimus in patients with the CYP3A5*1 genotype (extensive metabolizer). Ketoconazole, an inhibitor of CYP, leads to the reduction of the tacrolimus dose while maintaining therapeutic levels in transplant recipients. However, very few studies have mentioned coadministration of ketoconazole and tacrolimus in pediatric renal transplant recipients. Herein, we present a case of a 10-year-old boy with end-stage renal disease due to posterior urethral valves who underwent a living-related kidney transplant. We also emphasize the importance of CYP3A5 genotype evaluation in deciding the course of the treatment and maintaining therapeutic levels of tacrolimus in pediatric transplant recipients.

Effect of Wuzhi preparations on tacrolimus in CYP3A5 expressers during the early period after transplantation: A real-life experience from heart transplant recipients

BackgroundGenetic polymorphisms and drug interactions are associated with tacrolimus exposure. This study aimed to evaluate the effect of Wuzhi (WZ) preparations on tacrolimus (TAC) concentration and dose requirements in heart transplant recipients with the CYP3A5*1 allele during the early period after transplantation. MethodsA total of 167 adult heart transplant recipients with the CYP3A5*1 allele were included and divided into the WZ group (n = 115) and the WZ-free group (n = 52). Blood trough concentrations of TAC were detected and the dose-adjusted concentration (C0/D) and dose requirement for achieving the TAC therapeutic range were compared between the two groups. The change in C0/D and dose of TAC were evaluated before and after co-administration with WZ preparations. ResultsNo significant differences in TAC C0/D and dose requirement were observed between the WZ and WZ-free groups. However, the TAC C0/D in the WZ group was significantly increased an average of 2.10-fold after co-administration of WZ. Moreover, the degree of elevation was related to the dose of the active ingredient (Schisantherin A). Furthermore, ALT, AST, and TB levels were significantly reduced after administration of WZ preparations. ConclusionCo-administration of the WZ/TAC preparation, in heart transplant recipients carrying the CYP3A5*1 allele, considerably increased TAC concentration (C0/D) while decreased high levels of leading indicators in the liver function. More importantly, the effect of the WZ/TAC preparation on C0/D was a dose-dependent event. However, our finding needs to be further confirmed in a larger sample size.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

Influence of CYP3A4*22 and CYP3A5*3 combined genotypes on tacrolimus dose requirements in Egyptian renal transplant patients.

Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients. This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups. The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p= 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n= 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n= 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n= 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p< 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes. Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

Model-Based Tacrolimus Follow-up Dosing in Adult Renal Transplant Recipients: A Simulation Trial.

Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose. This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C 0,obs ), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C 0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C 0,pred ) were predicted. Of 190 tacrolimus C 0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C 0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C 0,pred ( P = 0.89). The median absolute difference between the tacrolimus C 0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C 0,obs versus 1.6 ng/mL for C 0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C 0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL). The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small.

CYP3A4/5 genotypes and age codetermine tacrolimus concentration and dosage in pediatric heart transplant recipients

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy for pediatric heart transplantation (HTx) recipients. However, little information is known on the interaction of developmental and genetic variants on TAC disposition in this population, which makes TAC dose optimization more difficult. The aim of study was to investigate the relationship between genotypes and age on TAC concentrations and dosage during the early post-operation period in pediatric HTx recipients. Sixty-six pediatric HTx recipients were enrolled and divided into three groups according to the age (<6, ≥6-≤12, 12–18 years old). CYP3A4/5, POR and ABCB1 polymorphisms were genotyped. The associations between genotypes and age on TAC dose-adjusted trough concentrations (C0/D), dose requirement as well as acute kidney injury (AKI) were evaluated. CYP3A5*3 and CYP3A4*1G were significantly correlated with TAC C0/D and dose requirement in the pediatric recipients ≥ 6 years. The C0/D in children aged ≥ 6-≤12 years and 12–18 years is 2.8 and 4.2 fold of these < 6 years old, respectively. TAC dose requirements in children aged < 6 years were 2.4 times and 3.5 times of these aged ≥ 6-≤12 years and 12–18 years, respectively. Among the same CYP3A5*3 or CYP3A4*1G genotypes, age was positively increased with TAC C0/D and negatively correlated with targeted dose. No genetic variants were found to be associated with AKI during the early post-operation period. CYP3A4/5 genotypes and age should be taken into consideration to TAC dosage in pediatric HTx recipients.