Evaluation of Four Automated Methods for Determination of Whole Blood Cyclosporine Concentrations

Hamwi, Ahmad; Veitl, Mario; Manner, Georg; Ruzicka, Katharina; Schweiger, Christian; Szekeres, Thomas

doi:10.1093/ajcp/112.3.358

Cited by 36 publications

(16 citation statements)

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“…Accuracy was 96% (400 mg l -1 ) and precision in the range applied (80-800 mg l -1 CsA) was described by the polynomial function: standard deviation = 1.2009 + 0.1278 3 . Compared with other immunoassays the FPIA (AxSYM) has low crossreactivity towards CsA metabolites: 5.5% (AM1), 13.7% (AM9), 2.1% (AM4n) and 2.5% (AM19) [33].…”

Section: Drug Analysismentioning

confidence: 99%

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Wilhelm¹,

Graaf²,

Veldkamp³

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT).• It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole).• Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS• A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIMTo develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODSThe pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTSTwenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h -1 (relative standard deviation [RSD] Ϯ 5.2%) with an inter-individual variability of 21%. The central volume of distribution (Vc) was 18.3 l (RSD Ϯ 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD Ϯ 9.9%) with and inter-individual variability of 25% and lag time (tlag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT...

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Section: Drug Analysismentioning

confidence: 99%

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Wilhelm¹,

Graaf²,

Veldkamp³

et al. 2012

Brit J Clinical Pharma

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“…The mean cyclosporine concentrations have [41][42][43][44][45][46] The FPIA assay for the application on the TDx analyzer (Abbott Laboratories) is no longer commercially available. More recently, Abbott Laboratories have marketed a CMIA for application on the Architect analyzer.…”

Section: Issues Of Interferences In Monitoring Of Immunosuppressantsmentioning

confidence: 99%

Impact of Interferences Including Metabolite Crossreactivity on Therapeutic Drug Monitoring Results

Dasgupta¹

2012

Therapeutic Drug Monitoring

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Therapeutic drug monitoring is an integral part of services offered by toxicology laboratories because certain drugs require routine monitoring for dosage adjustment to achieve optimal therapeutic response and avoid adverse drug reactions. Immunoassays are widely used for therapeutic drug monitoring. However, immunoassays suffer from interferences from both exogenous and endogenous compounds including metabolites of the parent drug. Digoxin immunoassays are affected more commonly than any other immunoassays used for therapeutic drug monitoring. Digoxin immunoassays are affected by endogenous digoxin-like immunoreactive substances and exogenous compounds such as various drugs, certain herbal supplements, and Digibind. Carbamazepine is metabolized to carbamazepine 10, 11-epoxide, and the crossreactivity of this metabolite with carbamazepine immunoassay may vary from 0% to 94%. Immunoassays used for measuring concentrations of tricyclic antidepressants are affected by tricyclic antidepressant metabolites and by a number of other drugs. Immunoassays for immunosuppressants are also subjected to significant interferences from metabolites, and liquid chromatography combined with mass spectrometry or tandem mass spectrometry is recommended for therapeutic drug monitoring of immunosuppressants. However, liquid chromatography combined with mass spectrometry may also suffer from interferences, for example, due to ion suppression or from isobaric ions.

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“…Many studies have been addressed specificity with regard to measurements of cyclosporine levels. [4][5][6][7][8] Recent studies have analyzed cyclosporine using HPLC-MS/ MS. [9][10][11][12] Also, some reports have been published on the simultaneous analysis of several immunosuppressant drugs (sirolimus, everolimus, and tacrolimus) [13][14][15][16][17] or the simultaneous analysis of cyclosporine metabolites. [18][19][20][21] These studies are time-consuming, and require many steps for sample preparation, including evaporation or reconstitution.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Determination of Cyclosporine in Human Whole Blood by Ultra-Performance Liquid Chromatography with Triple Quadrupole Tandem Mass Spectrometry

et al. 2014

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Cyclosporine is an immunosuppressant drug used in organ transplants or for the treatment of autoimmune diseases. We developed and validated a simple, sensitive, and specific method using UPLC-MS/MS to determine cyclosporine levels in human whole blood. MS/MS detection was performed in the positive electrospray ionization mode with multiple reaction monitoring. Cyclosporine was extracted from whole-blood samples using ascomycin as an internal standard. The mass transitions m/z 1203.49 → 1185.53 and m/z 814.71 → 796.67 were used to assay the analyte and IS. This method was validated with respect to linearity, specificity, accuracy, precision, recovery, and stability. The method exhibited a linear response from 10 to 1000 ng mL -1 with correlation coefficient values >0.99. The precision and the accuracy values were within 15%, except at the lower limit of quatification (LLOQ). Cyclosporine was stable in whole blood with no evidence of degradation. This method was successfully applied to a pharmacokinetic study of cyclosporine in healthy volunteers following oral administration.Keywords Cyclosporine, UPLC-MS/MS, human whole blood

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Evaluation of Four Automated Methods for Determination of Whole Blood Cyclosporine Concentrations

Cited by 36 publications

References 0 publications

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

Impact of Interferences Including Metabolite Crossreactivity on Therapeutic Drug Monitoring Results

Quantitative Determination of Cyclosporine in Human Whole Blood by Ultra-Performance Liquid Chromatography with Triple Quadrupole Tandem Mass Spectrometry

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