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: | R Jean Shapiro, Abby C. Collier, Mary H H Ensom, Nilufar Partovi, Tony K. L. Kiang, Jacob M. Berman |
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| Rok vydání: | 2018 |
| Předmět: |
medicine.medical_specialty
Population Renal function 030230 surgery Neutropenia 030226 pharmacology & pharmacy Gastroenterology Mycophenolic acid 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Pharmacology (medical) education Creatinine education.field_of_study medicine.diagnostic_test business.industry General Medicine medicine.disease Tacrolimus chemistry Therapeutic drug monitoring Absolute neutrophil count business medicine.drug |
| Zdroj: | Clinical Drug Investigation. 38:1011-1022 |
| ISSN: | 1179-1918 1173-2563 |
| Popis: | 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. 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. 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. 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: | OpenAIRE |
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