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 (AUC0-12 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 Emax model (EC50 = 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, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

Background Mycophenolic acid (MPA) exposure in pediatric kidney transplant patients receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyl transferases (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 (MPAG) concentrations from 32 patients were quantified by HPLC. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (pre-dose/trough and 20min, 1h and 3h post-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 and/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- and BSA-normalized MPA-AUC compared to carriers of no or only one UGT-SNP (P < 0.001 and P=0.01, respectively) (n=7). Dose- and BSA-normalized pre-dose MPA concentrations were 3.0- and 2.4-times higher, respectively (P < 0.001). Inter-individual 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.

Leukopenia and diarrhea are the predominant adverse events associated with mycophenolate mofetil (MMF), leading to dose reduction or discontinuation in children. Polymorphisms of the drug's main metabolizing enzyme, uridine diphosphate-glucuronosyl transferase (UGT), confer alteration in drug exposure. We studied the incidence of these polymorphisms in pediatric kidney transplant recipients experiencing MMF-associated leukopenia and diarrhea. UGT genotypes of 16 affected children who recovered after MMF dose reduction or discontinuation were compared with those of 22 children who tolerated the drug at standard doses. DNA was extracted and sequenced using standard procedures to detect polymorphisms associated with increased (e.g., UGT1A9 -331T>C) or decreased drug exposure. All three patients who were homozygous for UGT1A9 -331T>C developed leukopenia, and heterozygotes also had significantly more toxicity (P = 0.04). A weaker association (P = 0.08) existed in UGT2B7 -900G>A carriers. Our data implicate UGT polymorphisms associated with altered drug exposure as potential predictors of MMF adverse events.

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