Abstract/Details

Strategies for the optimization of immunotherapy in kidney transplantation


2007 2007

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Abstract (summary)

The success of kidney transplantation is dependent upon a life-long maintenance therapy with immunosuppressants. Immunosuppressants are narrow therapeutic index drugs that exhibit high intra and inter-individual variability in their pharmacokinetics (PK) and pharmacodynamics (PD). Immunosuppressant doses are adjusted by their concentrations, a practice referred to as 'therapeutic drug monitoring'. This dissertation aimed to devise novel strategies/methods to improve the monitoring of immunosuppressive agents and to compare their PK/PD between diabetic (D) and non-diabetic (ND) kidney transplant recipients.

A liquid chromatography tandem mass spectrometric assay was developed and validated to analyze the concentrations of mycophenolic acid (MPA) in saliva over a 12-hour dosing interval from 29 stable kidney transplant recipients. The MPA saliva concentrations were significantly associated with its total (r=0.322, p<0.001</italic>) or unbound (r=0.435, p<0.001 </italic>) plasma concentrations indicating that salivary MPA concentrations may prove to be a non-invasive method for its monitoring.

Pharmacokinetic characteristics of tacrolimus (TAC) and ciclosporin (CsA) were compared between D and ND patients. Tacrolimus maximum concentration (Cmax), time to maximum concentration (tmax) and the area under the concentration time curves (AUC0-12) were comparable between D and ND patients. In contrast, absorption of CsA was delayed (t max D=128.4 vs. ND=93 min, p=0.009], AUC0-12 was lower and the unbound fraction was higher (D=1.20% vs. ND=0.72%, p=0.066) in diabetic patients. The mechanism of differential effect of diabetes on the pharmacokinetics of CsA and TAC requires further characterization.

Pharmacodynamic properties of CsA and TAC were assessed using intracellular cytokine staining for IL-2, TNF-alpha and IFN-gamma in mitogen stimulated CD3+ T-lymphocytes. A strong correlation was observed between the expression of IL-2 with total CsA or TAC concentrations. The degree of immunosuppression was also compared between D (n=14) and ND (n=15) patients before dose and 2-hours after dose. B-cell activity was also determined by measuring fluorescence of surface markers CD54 (ICAM-1), CD86 (B7.2) and CD95 (Fas antigen) in pokeweed mitogen stimulated CD19 cells. Expression of intracellular IL-2 in CD3 cells was significantly lower in diabetics while CD95 in B-cells were significantly lower in diabetics both at resting and stimulated states. These results indicate that diabetics require lower concentrations of immunosuppressants than non-diabetics.

Indexing (details)


Subject
Pharmaceuticals;
Immunology
Classification
0572: Pharmaceuticals
0982: Immunology
Identifier / keyword
Health and environmental sciences; Ciclosporin; Diabetes; Immunosuppressants; Immunotherapy; Kidney transplantation; Mycophenolic acid; Tacrolimus; Therapeutic drug monitoring
Title
Strategies for the optimization of immunotherapy in kidney transplantation
Author
Mendonza, Anisha E.
Number of pages
168
Publication year
2007
Degree date
2007
School code
0186
Source
DAI-B 68/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549191391
Advisor
Akhlaghi, Fatemeh
University/institution
University of Rhode Island
University location
United States -- Rhode Island
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3276998
ProQuest document ID
304804922
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304804922
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