Therapeutic drug monitoring of sirolimus for optimal renal transplant outcomes

Kahan, Barry D.; Napoli, Kimberly L.; Podbielski, Jeanette; Hussein, I; Katz, Stephen M.; Buren, Charles T. Van

doi:10.1016/s0041-1345(00)02476-3

Cited by 11 publications

(5 citation statements)

References 4 publications

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“…Sirolimus has been studied in combination with calcineurin inhibitors (e.g. CsA or tacrolimus [12, 13]) and also with other immunosuppressive drugs (e.g. azathioprine or MMF [2, 4, 5]).…”

Section: Discussionmentioning

confidence: 99%

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Dansirikul

Duffull

Morris

et al. 2005

Brit J Clinical Pharma

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AimTo explore relationships between sirolimus dosing, concentration and clinical outcomes. MethodsData were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U -tests). ResultsSeveral patients experienced at least one episode when WBC ( n = 9), PLT ( n = 12), or HCT ( n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower ( P < 0.05) when sirolimus dose was greater than 10 mg day -1 , and sirolimus concentration greater than 12 m g l -1 . No relationship was shown for PLT and dichotomized sirolimus dose or concentration. ConclusionsGiven this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

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“…Sirolimus has been studied in combination with calcineurin inhibitors (e.g. CsA or tacrolimus [12, 13]) and also with other immunosuppressive drugs (e.g. azathioprine or MMF [2, 4, 5]).…”

Section: Discussionmentioning

confidence: 99%

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Dansirikul

Duffull

Morris

et al. 2005

Brit J Clinical Pharma

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“…The drug is administered orally as a once daily dose [1]. Individualization of treatment with sirolimus is based on assessment of whole blood trough concentrations [1–4]. After administration, sirolimus is rapidly absorbed from the gastrointestinal tract with a mean time (± SD) to reach maximum concentration ( t max ) of 1.4 h (± 1.2) [5].…”

Section: Introductionmentioning

confidence: 99%

A Bayesian approach for population pharmacokinetic modelling of sirolimus

Dansirikul

Morris

Tett

et al. 2005

Brit J Clinical Pharma

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AimsTo explore a Bayesian approach for the pharmacokinetic analysis of sirolimus concentration data arising from therapeutic drug monitoring (poorly informative concentration-time point design), and to explore possible covariate relationships for sirolimus pharmacokinetics. MethodsSirolimus concentration-time data were available as part of routine clinical care from 25 kidney transplant recipients. Most samples were taken at or near the trough time point at steady state. The data were analyzed using a fully conditional Bayesian approach with PKBUGS (v 1.1)/WinBUGS (v 1.3). Features of the data included noncompliance and missing concentration measurements below the limit of sensitivity of the assay. Informative priors were used. ResultsA two-compartment model with proportional residual error provided the best fit to the data (consisting of 315 sirolimus concentration-time points). The typical value for the apparent clearance (CL/ F ) was 12.5 l h − 1 at the median age of 44 years. Apparent CL was found to be inversely related to age with a posterior probability of a clinically significant effect of 0.734. ConclusionsA population pharmacokinetic model was developed for sirolimus using a novel approach. Bayesian modelling with informative priors allowed interpretation of a significant covariate relationship, even using poorly informative data.

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“…At this time the most successful agents for immunosuppression are the calcineurin inhibitors cyclosporin and tacrolimus. 2 There are a number of other immunosuppressive agents that are in phase III clinical trials, including sirolimus 3 and mycophenolate, 4 but their clinical e¤cacy and potential superiority over cyclosporin and tacrolimus are unproven.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporin: revisions in monitoring guidelines and review of current analytical methods

Andrews

Cramb

2002

Ann Clin Biochem

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This article summarizes the main changes that have occurred in cyclosporin (ciclosporin) monitoring and measurement since the previous review in this journal. Cyclosporin has been reformulated to reduce variability in its absorption, leading to fewer post-transplant rejection episodes. Monitoring has mostly utilized the measurement of pre-dose blood levels of the drug, but more recently the potential benefit of using samples collected during the first few hours post-dose has been evaluated. Calculating the area under the cyclosporin concentration-time curve may be the ideal, but is not viable in the routine clinical situation and 2-h post-dose sampling seems likely to offer a practical clinical solution. Analytical methods based on high-performance liquid chromatography (HPLC) and immunoassay are available for the determination of whole blood cyclosporin concentrations. HPLC is specific but rarely used for routine monitoring, although HPLC-tandem mass spectrometry is making the technique more viable. New immunoassays have been introduced, but none are completely specific for the parent drug and all exhibit cross-reactivity towards cyclosporin metabolites. Immunoassays were originally designed for the lower cyclosporin concentrations seen in pre-dose samples, but are being evaluated and modified for determination of the higher concentrations seen 2 h post-dose.

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Therapeutic drug monitoring of sirolimus for optimal renal transplant outcomes

Cited by 11 publications

References 4 publications

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

A Bayesian approach for population pharmacokinetic modelling of sirolimus

Cyclosporin: revisions in monitoring guidelines and review of current analytical methods

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