Introduction of cyclosporine (CsA) has improved the outcome of human organ transplants. However, the use of the drug has been beclouded by its low therapeutic efficacy: on the one hand due to significant inter-patient variations in drug absorption, distribution, metabolism and elimination (pharmacokinetics) and in immunosuppressive potency (pharmacodynamics); on the other hand, due to frequent drug-induced complications, particularly hepato- and nephrotoxicity. Because of the inconsistent clinical results obtained with the empiric use of CsA, the present application proposes to establish objective parameters for drug administration, in order to maximize therapeutic efficacy. Previous studies of CsA therapeutic drug monitoring, utilizing trough determinations by radioimmunoassay or by high performance liquid chromatography (HPLC), have not consistently predicted clinical events. This application proposes: a) pharmacokinetic profiling of allograft recipients with RIA, HPLC and enzyme-linked immunosorbent assay (ELISA), using a monoclonal antibody recognizing CsA; b) development of a model of Bayesian forecasting to predict chromatographic analysis of drug metabolites, including compounds 1, 17, 18, 21 described by Maurer, and metabolites of D and E described by the applicant group. Other metabolites of interest will be sought in a porcine model, wherein the animal is treated with drugs known to vitiate (rifampin) or potentiate (erythromycin) CsA actions and/or toxicities. Human serum, plasma, whole blood, urine and bile will be analyzed for the content of the distinctive moieties identified in the porcine models and correlated with therapeutic and toxic drug effects. Metabolites of interest will be used as immunogens to raise monoclonal antibodies that can be readily used to monitor transplant patients. Pharmacodynamic assays to quantitate immunosuppressive effect of CsA in man will examine both the kinetic profiles of CsA and related metabolites in the serum of patients, as well as inhibition of the capacity of transplant recipient lymphocytes to perform helper functions of interleukin-2 and gamma-interferon generation. The combined pharmacokinetic and pharmacodynamic approach will provide a foundation to design, monitor, evaluate and enhance with efficacy of CsA dosing regimens for renal, cardiac, hepatic and pancreatic transplant recipients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038016-02
Application #
3237110
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1986-12-01
Project End
1991-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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Chen, Wenhau; Langer, Robert M; Janczewska, Slawa et al. (2005) Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporine-induced nephrotoxicity. Transplantation 79:401-8
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Bai, Shuang; Stepkowski, Stanislaw M; Kahan, Barry D et al. (2004) Metabolic interaction between cyclosporine and sirolimus. Transplantation 77:1507-12
Kahan, Barry D (2004) Sirolimus-based immunosuppression: present state of the art. J Nephrol 17 Suppl 8:S32-9

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