Clinical relevance of post-transplant pharmacodynamic analysis of cyclosporine in renal transplantation

• Published in: International immunopharmacology 2014-10, Vol.22 (2), p.384-391
• Main Authors: Kurata, Yoko, Kuzuya, Takafumi, Miwa, Yuko, Iwasaki, Kenta, Haneda, Masataka, Amioka, Katsuo, Yamada, Kiyofumi, Watarai, Yoshihiko, Katayama, Akio, Uchida, Kazuharu, Kobayashi, Takaaki
• Format: Article
• Language: English
• Subjects: Adult; Antibodies; Cyclosporine; Cyclosporine - adverse effects; Cyclosporine - pharmacology; Cytomegalovirus - physiology; Female; Graft Rejection; Herpesvirus 3, Human - physiology; HLA Antigens - immunology; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacology; Kidney Diseases - chemically induced; Kidney Transplantation; Male; Middle Aged; Pharmacodynamics; Renal transplantation; T cell proliferation assay; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Virus Activation - drug effects
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2014.07.022

Although therapeutic drug monitoring based on blood concentration has been widely implemented in transplant recipients treated with immunosuppressive agents, clinical adverse events such as rejection, infection or drug-induced toxicity caused by inappropriate dosage cannot be completely controlled. Development of an effective assay for optimized immunosuppression would be desirable, which can potentially lead to personalized medicine in renal transplantation. Cyclosporine (CSA) pharmacodynamic analysis using carboxyfluorescein diacetate succinimidyl ester (CFSE)-based T cell proliferation assay was examined in 66 kidney transplant recipients before and after transplantation. Two parameters, the 50% inhibitory concentration (IC50) and the percentage of T-cell proliferation values at the lower plateau (bottom), were compared with clinical events. A significant relation in CSA pharmacodynamic parameters was observed between pre- and post-transplantation. Analysis of the association between clinical outcomes and pharmacodynamic parameters in post-transplant samples demonstrated the following findings: (i) cytomegalovirus (CMV)/varicella zoster virus (VZV) reactivation and CSA-induced nephrotoxicity were significantly associated with high sensitivity to CSA (low bottom or low IC50), (ii) acute T cell-mediated rejection (ATMR) was significantly related to low sensitivity to CSA (high bottom), and (iii) de novo human leukocyte antigen (HLA) antibody production was associated with lower bottom and IC50 values, although the elucidation of those mechanisms is still in progress. It was suggested that CSA pharmacodynamics applied at post-transplantation would be useful for optimizing immunosuppressive therapy. •T cell sensitivity to cyclosporine was examined in 66 renal transplant recipients.•CFSE-based T cell proliferation assay was performed before and after transplantation.•Pharmacodynamic parameters are related to clinical outcomes.•Clinical outcomes include viral reactivation, cyclosporine-induced nephrotoxicity and rejection.•Post-transplant pharmacodynamics is useful for optimizing immunosuppressive therapy.