This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Mycophenolate mofetil (CellCept , MMF) is a pro-drug that is rapidly hydrolyzed by esterases to the biologically active mycophenolic acid after oral administration. Mycophenolic acid (MPA) is an immunosuppressive agent that elicits its actions in a manner similar to azathioprine by inhibiting nucleic acid synthesis, although the mechanisms of these 2 agents differ. MPA produces potent, noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), thus blocking de novo synthesis of guanosine nucleotides; as lymphocytes depend upon the de novo pathway for purine synthesis, proliferative responses of T and B lymphocytes are blocked, and antibody formation and the generation of cytotoxic T-cells is inhibited. Recently, MMF efficacy and side effects have been linked to allelic variations in the gene of uridine diphosphonate-glucuronosyltransferase (UGT) 1A9, an key enzyme involved in MPA metabolism, suggesting that there may also be pharmacogenetic (PG) markers of MPA exposure. MMF has been approved in the United States for prophylaxis of organ rejection after allogeneic renal transplants. The Co-PI of this application, Dr. Vinks, is currently developing a pediatric population pharmacokinetic (PK) and pharmacodynamic (PD) model to predict MPA exposure and thus provide improved MMF dose individualization of children requiring renal transplantation. In parallel, PG studies are performed to identify additional predictors of MPA exposure. MMF is also frequently used off-label for the treatment of adults and children with systemic lupus erythematosus (SLE). Children with pediatric SLE (pSLE) almost always require prednisone for disease control. This is important as prednisone decreases MPA exposure. Results of MMF efficacy in pSLE have been variable, in part suggesting a very favorable safety/efficacy profile in pSLE but also that there is a considerable proportion of children with SLE who lack a clinical response to MMF. The exact mechanisms underlying these differential response patterns in pSLE have not been well examined. However, given the experiences in other diseases, we hypothesize that inter-individual differences in the PK and PD of MMF are prime factors for the observed differences in MMF efficacy with pSLE. What appears required are thorough PK, PD and PG studies in pediatric SLE populations to optimize the dosing of MMF to achieve inactive disease. The rationale of this study are such pharmacologic studies will allow for the development of evidence-based MMF dosing regimens for children with SLE that will enable ALL children with SLE to achieve the optimal therapeutic benefit from MMF. Study Objective: The primary objective of this study is to relate MMF exposure in SLE to disease control. Secondary objectives are to establish the impact of MPA on pharmacodynamic targets (IMPDH activity, mitogenesis and CD25 expression) and to obtain initial information about the potential importance of UGT 1A9 polymorphisms for pSLE response to MMF. This is an open-label, outpatient population, PK/PD/PG study of MPA in pediatric subjects diagnosed with SLE. The study will be conducted at Cincinnati Children's Hospital Medical Center (CCHMC).
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