Time-dependent pharmacokinetics of cyclosporine (NeoralR) in de novo renal transplant patients

Lukas, John C.; Suárez, Ana María Martín; Valverde, María P.; Calvo, María Victoria Martínez; Lanao, José M.; Calvo, Rosario; Súárez, Eduardo Viñuela; Gil, AP

doi:10.1111/j.1365-2710.2005.00683.x

Cited by 16 publications

(17 citation statements)

References 24 publications

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“…The concentration of CsA (10 À5 M), used in majority of the present in vitro study, is higher than the circulation level (0.3 $ 2.1 Â10 À6 M) in organ transplant recipients (Lukas et al, 2005). In the organ culture system, CsA 10 À6 M increased ET B mRNA expression (Fig.…”

Section: Discussionmentioning

confidence: 97%

Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

et al. 2015

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Section: Discussionmentioning

confidence: 97%

Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

et al. 2015

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“…[9][10][11] Interestingly, these adverse reactions were not more frequent in patients with higher mean blood concentrations, although the limited number of patients and the low predictive value of CsA trough concentrations used in our study should be taken into consideration. [12][13][14] A close observation of all vital signs and clinical symptoms of patients, which is recommended by label instructions during infusion (specifically during the first 30 min) did not occur for many of our patients because of the limited number of clinical staff. This fact could have affected the number patients who had these reactions.…”

Section: Discussionmentioning

confidence: 99%

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2015

Exp Clin Transplant

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Objectives: The use of cyclosporine for graft-versushost disease prophylaxis is a major factor in successful allogeneic hematopoietic stem cell transplantation. However, despite the drug being in clinical practice for more than 3 decades, there is no current global and consistent protocol for its optimal method of administration. In this study, we recorded situations related to cyclosporine administration and associated adverse reactions to aid in the development of more precise future guidelines. Materials and Methods: We monitored 22 candidates for allogeneic stem cell transplant during their hospitalization for a 1-year period, acquiring data recorded from predefined questionnaires prepared according to accredited literature, which included daily clinical and laboratory examinations. Results: Despite active attempts toward adherence to a standard protocol for cyclosporine administration, we found numerous occasions of deviations or mistakes, which may have led to adverse reactions. Conclusions: Our study, as one of the first published "drug utilization evaluations" for cyclosporine in stem cell transplant setting, proposes that educating involved clinical staff regarding a standard method of cyclosporine administration and providing efficient facilities would be highly valuable to implementation of a better practice.

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“…The adherence model was developed to mimic the 16 nonadherence patterns described by Russell et al9 This adherence model was coupled to a previously published population pharmacokinetic (dose-exposure) model that describes the within- and between-individual variability in the concentration-time profile of cyclosporine 3. The coupled simulation model was applied to determine variability in two measures of exposure: C avg and C min .…”

Section: Methodsmentioning

confidence: 99%

“…Shown is the median (solid line) and 90% population exposure range (shaded area) of cyclosporine serum concentration following a dose adjusted to a target trough concentration of 100–200 ng/mL. Derived from PK parameters reported in Lukas et al3…”

Section: Figurementioning

confidence: 99%

“…To maintain effective immunosuppression, C min values must be maintained above a floor of 100–200 ng/mL (the value defined in the US product label for the microemulsion formulation of cyclosporine). Figure 1 illustrates that after cyclosporine dose is adjusted to a trough of 100–200 ng/mL, the serum concentration will fall below that level if the next dose is delayed or missed 3. In contrast, over-exposure to high serum levels of cyclosporine is nephrotoxic, but the threshold at which this takes effect has not been clearly defined.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants

Maclean

Pfister²,

Zhou³

et al. 2011

TCRM

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Background and objectives:Nonadherence to oral immunosuppressive drugs in renal transplant patients remains a major challenge. The objective of this study was to develop an adherence-exposure model that 1) quantifies the impact of nonadherence patterns on cyclosporine levels and 2) identifies nonadherence patterns that are associated with unfavorable transplantation outcomes.Design, setting, participants, and measurements:This model quantified variability in drug exposure, expressed as the coefficient of variation (CV%), for time-averaged and trough cyclosporine levels (Cavg and Cmin, respectively), and percentage of days spent below the therapeutic Cmin target. Simulated patterns of nonadherence closely matched those observed in clinical practice for four nonadherence clusters and an “Others” category.Results:Patients in simulated nonadherence clusters 1–3 spent a mean (standard deviation) 5.8% (4.9), 9.0% (5.0), and 6.5% (3.4) of days below the Cmin target, compared with 76.8% (6.5) for cluster 4 and 38.3% (6.4) for the “Others” category. Mean (standard deviation) CV% values for Cmin were 24.1 (7.9), 35.4 (11.7), and 34.1 (10.6) for clusters 1–3, compared with 136.4 (23.6) for cluster 4 and 64.8 (10.3) for the “Others” category. Findings for Cavg were similar.Conclusion:Based on nonadherence patterns and known relationships between CV% for Cmin and Cavg, and transplantation outcomes, patients in cluster 4 and the “Others” category are expected to be at high risk of allograft rejection. The proposed drug adherence-exposure model is useful to identify high-risk patients who can be targeted for interventions aimed at enhancing drug adherence to optimize clinical long-term outcomes.

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Time-dependent pharmacokinetics of cyclosporine (NeoralR) in de novo renal transplant patients

Abstract: The PTD-dependent relative bioavailability model provides a rational means of steering dose titration of CsA in de novo renal transplantation patients by removing the large scale PK adjustment signal, either through nomograms or as a Bayesian prior.

Cited by 16 publications

References 24 publications

Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

Cyclosporin A upregulates ETB receptor in vascular smooth muscle via activation of mitogen-activating protein kinases and NF-κB pathways

Untitled

Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants

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