Abstract
Introduction
The immunosuppressive therapy with everolimus (ERL) after heart transplantation is characterized by a narrow therapeutic window and a substantial variability in dose requirement. Factors explaining this variability are largely unknown.
Objectives
Our aim was to evaluate factors affecting ERL metabolism and to identify novel metabolites associated with the individual ERL dose requirement to elucidate mechanisms underlying ERL dose response variability.
Method
We used liquid chromatography coupled with mass spectrometry for quantification of ERL metabolites in 41 heart transplant patients and evaluated the effect of clinical and genetic factors on ERL pharmacokinetics. Non-targeted plasma metabolic profiling by ultra-performance liquid chromatography and high resolution quadrupole-time-of-flight mass spectrometry was used to identify novel metabolites associated with ERL dose requirement.
Results
The determination of ERL metabolites revealed differences in metabolite patterns that were independent from clinical or genetic factors. Whereas higher ERL dose requirement was associated with co-administration of sodium-mycophenolic acid and the CYP3A5 expressor genotype, lower dose was required for patients receiving vitamin K antagonists. Global metabolic profiling revealed several novel metabolites associated with ERL dose requirement. One of them was identified as lysophosphatidylcholine (lysoPC) (16:0/0:0). Subsequent targeted analysis revealed that high levels of several lysoPCs were significantly associated with higher ERL dose requirement.
Conclusion
For the first time, this study describes distinct ERL metabolite patterns in heart transplant patients and detected potentially new drug–drug interactions. The global metabolic profiling facilitated the discovery of novel metabolites associated with ERL dose requirement that might represent new clinically valuable biomarkers to guide ERL therapy.
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Acknowledgements
We thank Barbara Rindlisbacher and Roland Geyer form the Clinical Metabolomics Facility at the Centre of Laboratory Medicine (Bern University Hospital) and Bjoern Schniedewind from the iC42 Clinical Research and Development Facility in Denver for technical support, as well as the personnel of the heart failure outpatient clinic at the Bern University Hospital for assistance in patient recruitment.
Funding
The study was funded by grants from the Foundation for Pathobiochemistry and Molecular Diagnostics of the German Society of Clinical Chemistry and Laboratory Medicine to J.S., from the United States National Institutes of Health (NICHD R01 HD070511) to U.C., and from the Katharina Huber-Steiner foundation to P.M.
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Dorothea Lesche and Vilborg Sigurdardottir are co-primary authors.
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Lesche, D., Sigurdardottir, V., Leichtle, A.B. et al. Targeted and global pharmacometabolomics in everolimus-based immunosuppression: association of co-medication and lysophosphatidylcholines with dose requirement. Metabolomics 14, 3 (2018). https://doi.org/10.1007/s11306-017-1294-8
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DOI: https://doi.org/10.1007/s11306-017-1294-8