Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients.

Autor: Kiang TKL; Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Room 3-142D, 11361-87 Ave, Edmonton, AB, T6G 2E1, Canada. tkiang@ualberta.ca., Partovi N; Department of Pharmacy, Vancouver General Hospital, Vancouver, BC, Canada.; Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada., Shapiro RJ; Department of Nephrology, Vancouver General Hospital, Vancouver, BC, Canada., Berman JM; Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada., Collier AC; Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada., Ensom MHH; Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: Clinical drug investigation [Clin Drug Investig] 2018 Nov; Vol. 38 (11), pp. 1011-1022.
DOI: 10.1007/s40261-018-0694-5
Abstrakt: Background and Objectives: The hematological side effects associated with mycophenolic acid (MPA) are relatively common and have severe consequences. The majority of literature data have not shown clear consistency in the MPA exposure-neutropenia relationship. We hypothesized that (i) adult de novo kidney transplant recipients who develop neutropenia have relatively higher dose-normalized MPA exposure than patients without neutropenia, and (ii) the observed neutropenia may be explained by polymorphisms in metabolism and/or transporter genes responsible for MPA disposition.
Methods: Adult kidney transplant recipients on steady-state tacrolimus and MPA, not receiving a corticosteroid, and with stable renal function were recruited for investigation at three periods post-transplant (1, 3, and 12 months; n = 21, 17, and 13, respectively). Clinical variables (age, weight, MPA daily dose, albumin, serum creatinine, absolute neutrophil count), tacrolimus and MPA concentrations (for exposure calculation), and genotypes (UGT2B7 G211T, UGT2B7 C802T, UGT1A9 T-275A, UGT1A9 T98C, MRP2 C-24T, MRP2 G1249A, OATP1B1 A388G, OATP1B1 C463A) were characterized.
Results: A significant inverse association between dose-normalized MPA exposure (a surrogate marker for apparent MPA clearance) and absolute neutrophil count in all three study periods (r 2  ~ 0.3-0.7) was observed. No associations between characterized single nucleotide polymorphisms and MPA exposure or absolute neutrophil count were established. However, significant alterations in the minor allele frequencies of UGT2B7*2 C802T, UGT1A9 T275A, and MRP2 G1249A were evident.
Conclusion: These findings support the clinical strategy for conducting MPA therapeutic drug monitoring in adult kidney transplant patients on steroid-free immunosuppressant therapy. The novel population genomic analysis data warrant further epidemiological investigations in a larger study sample.
Databáze: MEDLINE
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