Dorothea Lesche1,2, Vilborg Sigurdardottir3, Alexander B Leichtle1, Christos T Nakas1,4, Uwe Christians5, Lars Englberger6, Martin Fiedler1, Carlo R Largiadèr1, Paul Mohacsi7, Johanna Sistonen1. 1. University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 2. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. 3. Department of Cardiology, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 4. Laboratory of Biometry, University of Thessaly, Volos, Greece. 5. iC42 Clinical Research and Development, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA. 6. Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 7. Department of Cardiovascular Surgery, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. paul.mohacsi@insel.ch.
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.
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.
Authors: Nicola E Hiemann; Ernst Wellnhofer; Hans B Lehmkuhl; Christoph Knosalla; Roland Hetzer; Rudolf Meyer Journal: Transplantation Date: 2011-11-27 Impact factor: 4.939
Authors: Y Ji; S Hebbring; H Zhu; G D Jenkins; J Biernacka; K Snyder; M Drews; O Fiehn; Z Zeng; D Schaid; D A Mrazek; R Kaddurah-Daouk; R M Weinshilboum Journal: Clin Pharmacol Ther Date: 2010-11-24 Impact factor: 6.875
Authors: John M Kovarik; Howard Eisen; Richard Dorent; Donna Mancini; Mario Vigano; Marisel Rouilly; Chyi-Hung Hsu; Christiane Rordorf Journal: J Heart Lung Transplant Date: 2003-10 Impact factor: 10.247
Authors: Andrew S Levey; Lesley A Stevens; Christopher H Schmid; Yaping Lucy Zhang; Alejandro F Castro; Harold I Feldman; John W Kusek; Paul Eggers; Frederick Van Lente; Tom Greene; Josef Coresh Journal: Ann Intern Med Date: 2009-05-05 Impact factor: 25.391
Authors: Manuel A Hernández-Ruedas; Víctor Arroyo-Rodríguez; Jorge A Meave; Miguel Martínez-Ramos; Guillermo Ibarra-Manríquez; Esteban Martínez; Gilberto Jamangapé; Felipe P L Melo; Bráulio A Santos Journal: PLoS One Date: 2014-06-05 Impact factor: 3.240