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      Pharmacokinetic Advantages of Two-Hour Post-Dose Cyclosporin A Level for the Therapeutic Drug Monitoring in Stable Chinese Kidney Transplant Recipients

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          Background: Recent studies in Caucasian patients show that 2-hour post-dose cyclosporin A level (C2) monitoring has excellent correlation with the actual drug exposure and risk of rejection. However, the reliability of using C2 in stable Chinese renal transplant patients is unknown. Methods: Forty-nine stable Chinese renal transplant patients receiving microemulsion cyclosporin A (Neoral<sup>®</sup>) as part of their immunosuppressive therapy were recruited. Area under the time-concentration curve (AUC) was determined from whole blood cyclosporin A level taken at 0, 1, 2, 4 and 6 h post-dose at time 0 month. Cyclosporin A levels were repeated at 0, 1 and 2 h post-dose at 1 and 2 months later to determine the intra-individual variation at these specific time points. Results: The average duration of transplantation was 77 ± 42 months, with average daily cyclosporin dosage of 200 ± 43 mg in two divided doses. AUC has excellent correlations with cyclosporin A level at 1 h (C1) and 2 h (C2) (r = 0.81 and 0.82 respectively, p < 0.001 for both). The correlation between AUC and trough cyclosporin A level (C0) was statistically significant but only modest (r = 0.52, p < 0.001). On the other hand, the intra-individual coefficient of variation (CV<sub>w</sub>) of C1 was significantly larger than that of C2 (34.4 ± 24.2 vs. 15.9 ± 8.3%, p < 0.0001). Conclusion: We conclude that C2 level has favorable pharmacokinetic properties for therapeutic drug monitoring in stable Chinese transplant recipients. Both C1 and C2 have excellent correlation with AUC, but the intra-individual variability of C2 is much lower than that of C1.

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          Most cited references 25

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          Generation and application of data on biological variation in clinical chemistry.

          Most clinical chemical analytes vary in a random manner around a homeostatic set point. Replicate analyses of a series of specimens collected from a group of subjects allows estimation of analytical, within and between subject components of variation. The preferred experimental procedures and statistical methods for evaluation of data and analysis of variance are described; a detailed example is provided in the Appendix. The many uses of data on biological variation in clinical chemistry are reviewed, including setting analytical goals, deciding the significance of changes in serial results from an individual, evaluating the utility of conventional population-based reference values in patient management, and other applications.
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            The temporal profile of calcineurin inhibition by cyclosporine in vivo.

            Cyclosporine (CsA) acts by inhibiting the phosphatase calcineurin (CN), but the time course and extent of inhibition in vivo are unknown. We examined the effect of single oral CsA doses on CN activity in humans and mice in vivo. In humans, blood CsA levels were determined and CN activity was measured in whole blood and in blood leukocytes of patients up to 12 hr after CsA dosing (just before the second dose). Samples were collected from patients receiving a first single dose (2.5 mg/kg), and up to 14 days later after repeated dosing. In mice, after CsA dosing (12.5-200 mg/kg) by oral gavage, CsA levels in blood and tissue (spleen, kidney) were determined and CN activity was measured in spleen and kidney. In humans, peak CsA levels of 800-2285 microg/L at 1-2 hr produced 70-96% CN inhibition. Inhibition correlated closely with the rise and fall of CsA levels with no observable lag at the times sampled. Repeated doses showed similar CN inhibition to first dose, with no significant adaptation. In mice, CsA peaked at 1 hr in blood, spleen, and kidney, with higher concentrations in spleen and kidney than in blood. CN inhibition closely followed CsA concentrations/doses, and was greater in kidney than spleen. Thus CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation. The high CsA concentrations and CN inhibition in kidney may be relevant to nephrotoxicity.
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              Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation.

              To assess the importance of cyclosporine pharmacokinetics on graft outcome and acute rejection episodes, pretransplant and a total of 1868 posttransplant whole-blood cyclosporine pharmacokinetic profiles were performed in 160 consecutive kidney transplant recipients. The following posttransplant pharmacokinetic risk factors were associated with a poorer graft survival and a higher incidence of acute rejection: F, 325 ml/min; steady-state cyclosporine concentrations, < 350 ng/ml during intravenous infusion; or average cyclosporine concentrations, < 400 ng/ml during the first oral study. Although the discrimination between rejecting and nonrejecting patients was greatest for cyclosporine concentrations obtained at 24 hours after drug administration, measurements at 6 and 14 hours, as well as average concentrations, were all highly predictive. Because of the strong association between the cyclosporine concentrations and outcome, an equation is described to provide initial oral dose prediction. Furthermore, this association suggests that improved cyclosporine pharmacokinetic monitoring may aid in improving outcome after kidney transplantation.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                March 2005
                20 January 2005
                : 99
                : 3
                : c68-c72
                Departments of aMedicine & Therapeutics and bChemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
                83258 Nephron Clin Pract 2005;99:c68–c72
                © 2005 S. Karger AG, Basel

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                Figures: 2, Tables: 1, References: 29, Pages: 1
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