Review Articles: Focus on Pharmacodynamic Drug MonitoringPharmacodynamic Monitoring of mTOR InhibitorsMillán, Olga PhD*; Wieland, Eberhard MD†; Marquet, Pierre MD, PhD‡; Brunet, Mercè PhD*Author Information *Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center (CDB), CIBERehd, IDIBAPS, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain; †Zentralinstitut für Klinische Chemie und Laboratoriumsmedizin, Klinikum Stuttgart, Stuttgart, Germany; and ‡U1248 Pharmacology and Transplantation INSERM, CHU Limoges, University of Limoges, Limoges, France. Correspondence: Mercè Brunet, PhD, Pharmacology and Toxicology, Villarroel 170, Barcelona O8036, Spain (e-mail: [email protected]). The authors declare no conflict of interest. Therapeutic Drug Monitoring: April 2019 - Volume 41 - Issue 2 - p 160-167 doi: 10.1097/FTD.0000000000000616 Buy Metrics Abstract Pharmacodynamic (PD) monitoring may complement routine pharmacokinetic monitoring of mTOR inhibitors (mTORis) in an attempt to better guide individualized sirolimus (SRL) or everolimus (EVR) treatment after organ transplantation. This review focuses on current knowledge about PD biomarkers for personalized mTORi therapies. Different strategies have already been used in the evaluation of the pharmacodynamics of SRL and EVR as a proxy for their effects on the immune response after transplantation. These include measuring p70S6K (70 kDa ribosomal protein S6 kinase) activity, p70S6K phosphorylation (P-p70S6K), or P-S6 protein expression. Compared with Western blot and ELISA, phosphoflow cytometry can detect phosphorylated proteins and differentiate activation-induced changes of signaling molecules inside the cell from unstimulated populations of identical cells in the same sample. Alternatively, in patients receiving a combined therapy, the other PD approach is to consider biomarkers such as NFAT residual expression for calcineurin inhibitors or to evaluate nonspecific effects of the drugs such as lymphocyte proliferation, interleukin synthesis, specific peripheral blood T regulatory subsets, or lymphocyte surface antigens, which have the advantage to reflect the overall immunosuppressive status achieved. Although limited, the available data on mTOR pathway biomarkers seem promising. Before clinical implementation, the analytical methodologies must be standardized and cross-validated, and the selected biomarkers will have to demonstrate their clinical utility for SRL or EVR dose individualization in multicenter clinical trials. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.