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 (C0/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 C0/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, post-operative period and age was responsible for 65.3% of the variability in C0/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.

Figure 1

Linear regression relationships between urinary MR and the C₀/D and D/W ratios of tacrolimus across the different CYP3A5^*3 genotypes: (A) with the C₀/D ratio in overall subjects (n=231); (B) with the D/W ratio in overall subjects (n=231); (C) with the C₀/D ratio in CYP3A5^*1 carriers (n=58); (D) with the D/W ratio in CYP3A5^*1 carriers (n=58); (E) with the C₀/D ratio in CYP3A5^*3/^*3 genotype (n=173); (F) with the D/W ratio in CYP3A5^*3/^*3 genotype (n=173).