title: Therapeutic Drug Monitoring of Everolimus: A Consensus Report.
abstract: In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.
authors.affiliation: *Klinikum Stuttgart, Zentralinstitut für Klinische Chemie und Laboratoriumsmedizin, Stuttgart, Germany; †Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; ‡Analytical Services International, London, United Kingdom; §Pharmacology, APHP, Hôpital Européen G Pompidou, Paris Descartes University, Paris, France; Departments of ¶Internal Medicine and ‖Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; **Clinical Pharmacology Unit, Institute of Cardiology, Warsaw, Poland; ††Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, Spain; ‡‡Medizinische Klinik mit Schwerpunkt Nephrologie, Charité Universitätsmedizin Berlin, Berlin, Germany; §§Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; ¶¶Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical Hospital, Pisa, Italy; ‖‖Pharmacology and Toxicology Laboratory (CDB), CIBERehd, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain; ***Department of Pharmacy, Kyushu University Hospital, Kyushu University, Fukuoka, Japan; †††Department of Clinical Pharmacology & Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; ‡‡‡Risch Laboratories Group, Schaan, Principality of Liechtenstein; §§§UMR 850 INSERM, University of Limoges, CHU Limoges, Limoges, France; ¶¶¶Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany; ‖‖‖Toxicology and Drug Monitoring Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, College of Medicine, Rochester, MN; ****Clinical Chemistry Department, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium;
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mesh_terms: D065095:Calcineurin Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D002138:Calibration; D016903:Drug Monitoring; D000068338:Everolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000068338:Everolimus