Abstract:
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 (r2 ~ 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.
journal_name
Clin Drug Investigjournal_title
Clinical drug investigationauthors
Kiang TKL,Partovi N,Shapiro RJ,Berman JM,Collier AC,Ensom MHHdoi
10.1007/s40261-018-0694-5subject
Has Abstractpub_date
2018-11-01 00:00:00pages
1011-1022issue
11eissn
1173-2563issn
1179-1918pii
10.1007/s40261-018-0694-5journal_volume
38pub_type
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