UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients

Abstract

Background: Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.

Methods: MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C.

Results: Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05).

Conclusion: Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

Figure 1. Relationship between the genotype group and A) Estimated MPA AUC_0–12 and B) Estimated C_trough

Sixteen recipients are included in this analysis, who are ≥ 7 years old, on more than 354.7mg/m² MMF dose and not a carrier of UGT1A9-2152 C>T and UGT1A8*3. They are divided into three groups as follows: Group 1: Recipients with no or only one UGT-SNP, and no MRP2-24T>C, Group 2: MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G, Group 3: Heterozygotes for MRP2-24T>C who also had UGT1A9-440C>T and/or UGT2B7-900A>G. Horizontal lines indicate 25, 50 and 75 percentiles.

Figure 2. Association between estimated MPA C_max and UGT1A9-440/-331 genotype

Twenty five recipients who are ≥ 7 years old and not a carrier of UGT1A9-275T>A and/or UGT1A8*3 are included in this analysis. Sixteen recipients were on more than 354.7mg/m² MMF dose (lift) and 9 recipients were less than 354.7mg/m² MMF dose (right).