title: Clinical relevance of post-transplant pharmacodynamic analysis of cyclosporine in renal transplantation.
abstract: 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.
authors: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan; Department of Clinical Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan; Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan.
authors: Yoko
authors: Y
authors: Kurata
authors: Japanese Red Cross Aichi Blood Center, Seto, Japan.
authors: Takafumi
authors: T
authors: Kuzuya
authors: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan.
authors: Yuko
authors: Y
authors: Miwa
authors: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan.
authors: Kenta
authors: K
authors: Iwasaki
authors: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan.
authors: Masataka
authors: M
authors: Haneda
authors: Department of Clinical Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan.
authors: Katsuo
authors: K
authors: Amioka
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan.
authors: Kiyofumi
authors: K
authors: Yamada
authors: Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
authors: Yoshihiko
authors: Y
authors: Watarai
authors: Department of Transplant Surgery, Masuko Memorial Hospital, Nagoya, Japan.
authors: Akio
authors: A
authors: Katayama
authors: Department of Transplant Surgery, Aichi Medical University, Nagakute, Japan.
authors: Kazuharu
authors: K
authors: Uchida
authors: Department of Transplant Immunology, Nagoya University School of Medicine, Nagoya, Japan. Electronic address: takakoba@med.nagoya-u.ac.jp.
authors: Takaaki
authors: T
authors: Kobayashi
mesh_terms: D000328:Adult; D000906:Antibodies; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000502:physiology; D005260:Female; D006084:Graft Rejection; D006680:HLA Antigens / Q000276:immunology; D014645:Herpesvirus 3, Human / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014775:Virus Activation / Q000187:drug effects
chemical_list: D000906:Antibodies; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D016572:Cyclosporine
keywords: Cyclosporine; Pharmacodynamics; Renal transplantation; T cell proliferation assay