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

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.

Inosine monophosphate dehydrogenase (IMPDH) activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients.

Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC(0-12 h)) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E(max) model (EC(50) = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.