Mycophenolic acid pharmacogenomics in kidney transplantation

Abstract

Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed to prevent acute rejection in kidney transplantation. MPA reversibly inhibits the enzymes involved in the synthesis of guanosine nucleotides, thus preventing DNA replication of immune cells. Consequently, the repression of both cell and humoral immunity induces renal allograft tolerance. MPA is an effective and safe immunosuppressive drug, but some patients show variability in drug concentration, acute rejection, graft dysfunction, or MPA-related adverse events. Although the pharmacogenomics of immunosuppressive drugs has been widely investigated, MPA has been explored to a lesser extent. This review of MPA pharmacogenomic studies, included pharmacokinetics, adverse events, and main clinical outcomes of MPA treatment in kidney transplantation. Associations of variants in genes encoding MPA metabolizing enzymes, transporters, and targets with drug efficacy and safety are described. Most pharmacogenetic studies have focused on small sample sizes and few simultaneously analyzed genetic variants. Some studies reported significant associations of pharmacokinetics-and pharmacodynamics-related genes with MPA exposure, acute rejection, graft dysfunction, hematological events, and gastrointestinal complications. However, even large cohorts did not replicate the findings, possibly due to divergent study design, immunosuppressive scheme, follow-up time, and other factors. Finally, the heterogeneity of aspects between studies limit conclusions on pharmacogenetic biomarkers of MPA in kidney transplantation.

Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients

“…The novel pharmacogenomic analysis of ABCC2 haplotype associations with mycophenolic acid pharmacokinetic parameters (phenotypes) includes exposure (AUC 0‐12h ), clearance, and the ratio of mycophenolic acid glucuronide AUC 0‐12h to mycophenolic acid AUC 0‐12h , as an objective end point of enterohepatic circulation. Further pharmacogenomic interrelationships with mycophenolic acid pharmacokinetics are described in further detail in these recent reviews 12,14,17 …”

“…Diagram showing mycophenolic acid metabolic pathway (from Genvigir et al 17 ). The multidrug resistance‐associated protein 2 encoded by the ABCC2 gene is responsible for the excretion of MPAG and Ac‐MPAG into bile.…”

“…Further pharmacogenomic interrelationships with mycophenolic acid pharmacokinetics are described in further detail in these recent reviews. 12,14,17 Interestingly, 51% of the combined group (those receiving either cyclosporine or tacrolimus) were estimated to carry at least 1 copy of the wild-type ABCC2 haplotype CGC. The mycophenolic acid AUC 0-12h associated with this wild-type haplotype ranged from 27.83 to 34.30 mg•h/L, which is at the lower therapeutic range for mycophenolic acid target exposure of 30-60 mg•h/L for all participants.…”

“…This enterohepatic recycling contributes 10% to 60% to total mycophenolic acid exposure (AUC 0‐12h ) over the dosing interval 7,8 . Multidrug resistance protein 2 is also expressed in the renal proximal tubules and contributes to urinary excretion of primarily mycophenolic acid glucuronide 2,16,17 . Therefore, the multidrug resistance protein 2 transporter modulates mycophenolic acid and mycophenolic acid glucuronide systemic exposure with immunosuppression posttransplant.…”

Pharmacogenetics and pharmacogenomics in human diseases

“…Pandey et al [5] studied the problems with hydroxyurea treatment in sickle cell disease and how to overcome or minimize myelosuppression and DDIs, postulating a mathematical model to challenge interpatient variability, dose optimization, and non-adherence.…”