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Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
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Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.

C Damon1, M Luck1,2, L Toullec3

  • 1Hypercube Institute, Paris, France.

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
|September 7, 2016
PubMed
Summary

Genetic variants influence how much tacrolimus (Tac) patients need. This study identified key genes, including SLC28A3, that predict individual Tac dose requirements in kidney transplant recipients.

Keywords:
clinical research/practicegeneticsgenomicsimmunosuppression/immune modulationimmunosuppressive regimenspharmacologytranslational research/science

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Area of Science:

  • Pharmacogenomics
  • Transplant Medicine
  • Genetics

Background:

  • Drug metabolism and response vary significantly between individuals.
  • Tacrolimus (Tac) dose requirements exhibit substantial interindividual variability, impacting transplant outcomes.
  • Understanding the genetic basis of drug metabolism is crucial for personalized medicine.

Purpose of the Study:

  • To identify single-nucleotide polymorphisms (SNPs) that predict variability in tacrolimus (Tac) dose requirements.
  • To develop a robust predictive model for Tac C0 using genetic data.
  • To uncover key genes and molecular pathways involved in Tac metabolism.

Main Methods:

  • A high-throughput genetic approach was used in 229 kidney transplant recipients.
  • Tacrolimus blood concentrations (Tac C0) were monitored for 3 months post-transplantation.
  • An original predictive approach integrating ensemble variable selection and multivariate modeling was developed to handle high-dimensional genomic data.

Main Results:

  • Predictive models explained up to 70% of Tac C0 variability per dose using a maximum of 44 gene variants (p < 0.001).
  • Identified molecular networks involved oxidoreductase activities and the ABCC8 transporter.
  • An intronic variant in SLC28A3, a drug transporter gene, was identified as a key predictor and validated in an independent cohort.

Conclusions:

  • Genetic variations, particularly in SLC28A3, significantly influence tacrolimus dose requirements.
  • The developed predictive models offer a promising tool for optimizing Tac dosing in kidney transplant patients.
  • This study highlights the importance of pharmacogenomics in tailoring immunosuppressive therapy.