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Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified in the genes encoding CYP3A4 , CYP3A5 , and ABCB1 , including CYP3A4-392A/G (rs2740574), CYP3A5 6986A/G (rs776746), and ABCB1 3435C/T (rs1045642). This study aims to evaluate the association among CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T polymorphisms and TAC, serum concentration, and biochemical parameters that may affect TAC pharmacokinetics in Mexican kidney transplant (KT) patients., Methods: Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and ABCB1 gene polymorphisms were genotyped using qPCR TaqMan. Serum TAC concentration (as measured) and intervening variables were assessed. Logistic regression analyses were performed at baseline and after one month to assess the extent of the association between the polymorphisms, intervening variables, and TAC concentration., Results: The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13-21.9; p = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54-93.08; p = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79-88.23; p = 0.018) were strongly associated with TAC pharmacokinetic variability., Conclusion: The findings of this study of the Mexican population showed that CYP3A5-6986 A/G GG genotype is associated with a four-fold increase in the likelihood of encountering a TAC concentration of more than 15 ng/dL. The co-occurrence of the CYP3A5-6986GG genotype and the use of drugs that increase TAC concentration correlates with a nine-fold increased risk of experiencing a TAC at a level above 15 ng/mL. Therefore, these patients have an increased susceptibility to TAC-associated toxicity.

Abstract: Objective: Therapies for end-stage renal disease improve quality of life, and survival. In Mexico, clinicians often must choose between different therapies without the availability of comparative outcomes evaluation. The present study evaluates the comparative cost-utility of sirolimus (SIR) versus tacrolimus (TAC) for the primary prevention of graft rejection in renal transplant recipients in Mexico. Methods: We used modeling techniques to estimate the cost-effectiveness of SIR versus TAC to prevent graft rejection in patients with end-stage renal disease in the Mexican setting. The model estimates the cost of quality-adjusted life-year (QALY) per patient. We applied a 20-year horizon (1-year Markov cycles). Cost-effectiveness was expressed in terms of cost per QALY. All costs are presented in 2011 US dollars. Probabilistic sensitivity analyses were conducted. Results: The total cost for the SIR treatment arm over the 20-year duration of the model is estimated to be $136,778. This compares with $142,624 for the TAC treatment arm, resulting in an incremental cost of SIR compared with that of TAC of−$5,846. Over 20 years, SIR was estimated to have 8.18 QALYs compared with 7.33 QALYs for TAC. The resulting incremental utility of SIR compared with that of TAC is 0.84 QALY gained. SIR is estimated to be both less costly and more effective than TAC, indicating that it is the dominant strategy. Notably, results suggest that SIR has a 78% probability of being dominant over the TAC strategy and a 100% probability of having an incremental cost-effectiveness ratio at or below $10,064 (1 GDP) per QALY. Conclusions: These analyses suggest that in the Mexican setting, the use of SIR in place of TAC for the prevention of graft rejection in this population is likely to be cost saving. [Copyright &y& Elsevier]

Background and Aims: Variability in CYP3A5 expression associated with differences in tacrolimus bioavailability has been documented. The wild-type allele CYP3A5*1 expresses the functional protein, whereas the CYP3A5*3 allele is a splice variant with a premature stop codon and encodes a truncated nonfunctional protein. The aim of the study was to determine the frequency of CYP3A5*1 and CYP3A5*3 in 291 (124 adults, 167 pediatric) Mexican renal transplant recipients, evaluate the tacrolimus dose requirements by genotype and compare genotype frequency data with that of other populations. Methods: We carried out a multicenter study. Patients were recruited from three institutions located in Mexico City. Genotyping of the CYP3A5*1 and CYP3A5*3 alleles was performed by direct DNA sequencing. Results: Eighteen patients (6.2%) were CYP3A5*1*1 homozygous carriers or functional protein expresser homozygous, 121 patients (41.6 %) were CYP3A5*1*3 were heterozygous carriers or heterozygous expressers, and 152 patients (52.2%) were CYP3A5*3*3 homozygous carriers or homozygous nonexpressers. There was a statistically significant difference in frequency of the functional and nonfunctional expresser phenotypes from those reported for Black and Caucasian, but not for South Asian populations. The CYP3A5 phenotype had a significant impact in tacrolimus bioavailability, as wild-type carriers required higher dosing compared to mutated carriers to achieve similar drug trough levels. Patients with CYP3A5*1*1 genotype had a median dose requirement of 0.16 mg/kg/day, CYP3A5*1*3 patients had a median tacrolimus dose of 0.13 mg/kg/day and CYP3A5*3*3 had a median dose of 0.07 mg/kg/day (Kruskal–Wallis, p <0.0001). Conclusions: Of the Mexican transplant recipients, 52.2% were CYP3A5*3*3 and required significantly lower tacrolimus dose than those with CYP3A5*1 allele. [ABSTRACT FROM AUTHOR]

Background: The vigilance of tacrolimus (TAC) trough levels is an essential part of renal transplant follow up. Reduced TAC trough levels and high variability are related to adverse outcomes. The aim of this study was to evaluate the impact of brand changes on tacrolimus (TAC) subtherapeutic (SubT) trough levels, acute rejection (AR), and kidney function. Methods: This is a prospective, observational cohort study of renal transplant recipients, between January 2016 and October 2018. Tacrolimus trough levels and brand used by the patient were both registered at every consult. Tacrolimus values ≤3.5 ng/mL were considered SubT. Results: 445 patients were included. The median number of TAC brand changes was 2 (IQR, 1‐4). Patients were grouped according to the number of brand changes: Group 1 = 0 (n = 107), Group 2 = 1‐4 (n = 236), and Group 3 = ≥5 (n = 102). Patients with the greatest number of brand changes had a greater proportion and number of SubT TAC trough levels (Group 1 = 36.4%, average 0.53; Group 2 = 39.8%, average 0.65, Group 3 = 59.8%, average 1.17, P <.001) and AR (Group 1 = 0.9%, Group 2 = 11%, Group 3 = 14.7%, P <.001). On multivariate analysis, SubT levels and the number of brand changes were related to AR. Conclusions: In Mexico, changes in TAC brand are associated with an elevated frequency of SubT levels. Brand changes and SubT levels are independently associated with acute rejection. The supply policies on TAC brands in Mexico require revision to avoid changing brands as much as possible. [ABSTRACT FROM AUTHOR]

TDM of tacrolimus is usually performed with trough levels (C0h). However, in pediatric patients, C0h may not be an adequate marker. The AUC is considered a more suitable indicator of drug exposure. As several blood samples are needed for the estimation of AUC, and LSS for predicting tacrolimus AUC and optimizing the dose adjustment have been proposed. Moreover, in emerging countries such as Mexico, non‐innovator formulations, which bioequivalence has not been demonstrated, are frequently used. Hence, the aim of this study was to develop and validate a LSS to predict the tacrolimus AUC0‐12h in Mexican pediatric kidney transplant recipients who received either Prograf® or non‐innovator tacrolimus formulations. A total of 56 pharmacokinetic profiles were randomized into two groups: model development (n = 28) and model validation (n = 28). The limited sampling equations were obtained after a stepwise multiple regression using AUC as the dependent variable and tacrolimus blood concentrations, quantified by CMIA, at different time points as the independent variables. The final equation included observed concentrations at 1 hour (C1h) and 4 hours (C4h) after dose administration. The predictive performance of the model was adequate in terms of both, bias and precision. Results strongly suggest that the clinical use of this LSS could provide an ethical, cost‐, and time‐effective method in the TDM of tacrolimus in pediatric patients with kidney transplant. The model proved to be adequate with either Prograf® or non‐innovator tacrolimus formulations of dubious bioequivalence. [ABSTRACT FROM AUTHOR]

TDM of tacrolimus is usually performed with trough levels (C 0h ). However, in pediatric patients, C 0h may not be an adequate marker. The AUC is considered a more suitable indicator of drug exposure. As several blood samples are needed for the estimation of AUC, and LSS for predicting tacrolimus AUC and optimizing the dose adjustment have been proposed. Moreover, in emerging countries such as Mexico, non-innovator formulations, which bioequivalence has not been demonstrated, are frequently used. Hence, the aim of this study was to develop and validate a LSS to predict the tacrolimus AUC 0-12h in Mexican pediatric kidney transplant recipients who received either Prograf ® or non-innovator tacrolimus formulations. A total of 56 pharmacokinetic profiles were randomized into two groups: model development (n = 28) and model validation (n = 28). The limited sampling equations were obtained after a stepwise multiple regression using AUC as the dependent variable and tacrolimus blood concentrations, quantified by CMIA, at different time points as the independent variables. The final equation included observed concentrations at 1 hour (C 1h ) and 4 hours (C 4h ) after dose administration. The predictive performance of the model was adequate in terms of both, bias and precision. Results strongly suggest that the clinical use of this LSS could provide an ethical, cost-, and time-effective method in the TDM of tacrolimus in pediatric patients with kidney transplant. The model proved to be adequate with either Prograf ® or non-innovator tacrolimus formulations of dubious bioequivalence., (© 2019 Wiley Periodicals, Inc.)

The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in Mexican adult kidney transplant patients to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one-compartment model and the First Order Conditional Estimation method with Interaction (FOCEI via NONMEM v.7.3.). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of haematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Interindividual variability associated with tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate the stability of the final model; external validation was performed in a new group of patients (n = 13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on haematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Aims: The aims of this study were (i) to develop a population pharmacokinetic (PK) model of tacrolimus in a Mexican renal transplant paediatric population (n = 53) and (ii) to test the influence of different covariates on its PK properties to facilitate dose individualization., Methods: Population PK and variability parameters were estimated from whole blood drug concentration profiles obtained at steady-state using the non-linear mixed effect modelling software NONMEM® Version 7.2., Results: Tacrolimus PK profiles exhibited high inter-patient variability (IPV). A two compartment model with first order input and elimination described the tacrolimus PK profiles in the studied population. The relationship between CYP3A5 genotype and tacrolimus CL/F was included in the final model. CL/F in CYP3A5*1/*1 and *1/*3 carriers was approximately 2- and 1.5-fold higher than in CYP3A5*3/*3 carriers (non-expressers), respectively, and explained almost the entire IPV in CL/F. Other covariates retained in the final model were the tacrolimus dose and formulation type. Limustin® showed markedly lower concentrations than the rest of the formulations., Conclusions: Population PK modelling of tacrolimus in paediatric renal transplant recipients identified the tacrolimus formulation type as a significant covariate affecting the blood concentrations and confirmed the previously reported significant effect of CYP3A5 genotype on CL/F. It allowed the design of a proposed dosage based on the final model that is expected to help to improve tacrolimus dosing., (© 2015 The British Pharmacological Society.)

The aim of this study was to evaluate the bioavailability of two oral tacrolimus formulations, the innovator Prograf(®) and a formulation commercialized in Mexico with the brand name Limustin(®), in children. Stable Mexican pediatric renal transplant recipients received the product authorized by their social security provider, being either Prograf(®) or Limustin(®). At steady state, blood samples were drawn and tacrolimus blood concentration against time curves was constructed. CYP3A5 genotype was also determined. There was no significant difference in dose or in trough concentrations between formulations. However, AUC and Cmax were significantly higher with Prograf(®). The lower tacrolimus bioavailability with Limustin(®) was observed in both expressers and non-expressers of the functional CYP3A5 protein. Dose-normalized AUC values in expressers were 12.7 ± 11.9 and 48.7 ± 20.4 ng·h/mL/mg for Limustin(®) and Prograf(®), whereas in non-expressers, dose-normalized AUC was 54.4 ± 49.1 and 110.4 ± 42.9 ng·h/mL/mg for Limustin(®) and Prograf(®), respectively (p < 0.05). Pharmaceutical quality analysis showed that Limustin(®) dissolution at 120 min was 31.1 ± 6.2% while Prograf(®) dissolution was 100 ± 4.8%. Furthermore, the mean percentage of labeled amount of Limustin(®) and Prograf(®) was 91.0 ± 3.1% and 100.0 ± 0.7%, respectively. Hence, Limustin(®) exhibits pharmaceutical characteristics dissimilar to the innovator that likely explain the reduced tacrolimus exposure in children. We consider Limustin(®) is not adequate for pediatric use., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)