Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

Abstract

Aim: To examine how the endogenous CYP3A4 phenotype and CYP3A5*3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C 0 /D) and weight-corrected daily dose (D/W) of tacrolimus. Methods: A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5*3 genotype was determined using PCR-RELP. Results: In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and post-operative period accounted for 60.1% of the variability in C 0 /D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5*3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5*3/*3 subjects, a combination of the endogenous CYP3A4 phenotype, postoperative period and age was responsible for 65.3% of the variability in C 0 /D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range. Conclusion: This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5*3 genotype and other non-genetic variables.

Incorporation of Gene‐Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients

“…As mentioned before, variants of CYP3A5 and CYP3A4 are major determinant in tacrolimus disposition . In white ancestry it was reported that the CYP3A5 genotype could explain about 30% and CYP3A4 activity accounts for 25% of variability in tacrolimus dose requirement and clearance, and similar results were obtained in a Chinese cohort . Moreover, a strong linkage disequilibrium between the CYP3A4 rs2242480 and CYP3A5 rs776746 polymorphism was reported by several studies …”

A novel random forest integrative approach based on endogenous CYP3A4 phenotype for predicting tacrolimus concentrations and dosages in Chinese renal transplant patients

“…As discussed above, however, genetic information has its own limitations. And so, the enzyme probes, which are used to estimate the patient's metabolic activity, may enable the optimization of tacrolimus dosing for an individual patient as a complementary strategy …”

“…However, administration of midazolam would introduce potential inconvenience to patients because of the pharmacological effects as a central nervous system depressant; thus, the use of endogenous substances as biomarkers of CYP3A4 phenotype is the simplest and safest way to sequentially monitor in vivo CYP3A4 activity. In our previous study, an endogenous CYP3A4 probe assessed by urinary HOM was developed in renal transplant recipients . The previous findings also suggested that the relationships between tacrolimus metabolism and some of clinical variables were complex due to significant differences in the physical condition of patients .…”

“…In our previous study, an endogenous CYP3A4 probe assessed by urinary HOM was developed in renal transplant recipients . The previous findings also suggested that the relationships between tacrolimus metabolism and some of clinical variables were complex due to significant differences in the physical condition of patients . As a multivariate statistical model, RF algorithm that depended on the combination of individual parameters (Table ) might be a useful approach to describe these complicated relationships.…”

“…However, such genetic information is not capable of explaining the residual inter‐individual variability in the pharmacokinetics of tacrolimus within CYP3A5 expressers or CYP3A5 non‐expressers, and therefore, the achievement of an individual's dosing regimen based on genetic assays remains limited . As a complementary or alternative strategy, an endogenous CYP3A4 phenotype [assessed by the combined ratio of 6β‐hydroxycortisol and 6β‐hydroxycortisone to cortisol and cortisone in urine (HOM)] has been developed in our laboratory to determine in vivo CYP3A4 activity, which may serve as an effective strategy to overcome the limitations of genetic approaches . Taking into account advantages of endogenous CYP3A4 phenotype, urinary HOM is a truly non‐invasive biomarker for tacrolimus metabolism in renal transplant patients because of unnecessary administration of probe drugs to human and no serial blood sampling .…”