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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

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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.

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Acknowledgements

We sincerely thank Trana Hussaini for assistance in patient recruitment.

Author information

Authors and Affiliations

  1. 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

    Tony K. L. Kiang

  2. Department of Pharmacy, Vancouver General Hospital, Vancouver, BC, Canada

    Nilufar Partovi

  3. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada

    Nilufar Partovi, Jacob M. Berman, Abby C. Collier & Mary H. H. Ensom

  4. Department of Nephrology, Vancouver General Hospital, Vancouver, BC, Canada

    R. Jean Shapiro

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  6. Mary H. H. Ensom
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Corresponding author

Correspondence to Tony K. L. Kiang.

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Funding

This study was supported by an unrestricted educational grant from Hoffmann-La Roche Limited (principal investigator: Mary H.H. Ensom) and the 2015 Vancouver Coastal Health Research Institute Team Grant Award (principal investigator: Tony K.L. Kiang). No editorial assistance was received for the preparation of this article.

Conflicts of interest

Nilufar Partovi, R. Jean Shapiro, Jacob M. Berman, and Abby Collier report no conflicts of interest related to the publication of this article. Tony K.L. Kiang and Mary H.H. Ensom held grant supports as detailed above (which did not pose a conflict of interest with this article), and do not report any other conflicts of interest.

Ethics Approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments). Ethics and operation approval were obtained from the University of British Columbia Clinical Research Ethics Board and Vancouver Coastal Health Research Institute, respectively.

Informed Consent

Written informed consent was obtained from all individual participants included in the study.

Data Source

Original data can be made available upon request to the corresponding author.

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Kiang, T.K.L., Partovi, N., Shapiro, R.J. et al. 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. Clin Drug Investig 38, 1011–1022 (2018). https://doi.org/10.1007/s40261-018-0694-5

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