Development and Validation of Limited Sampling Strategies for Estimation of Cyclosporine Area Under the Concentration–Time Curve in Hematopoietic Stem Cell Transplant Patients

Abstract

The aim of this study was to develop and validate limited sampling strategies for accurately predicting 12-hour area under the concentration-time curve (AUC(0-12 h)) to provide a practical method for more precise therapeutic drug monitoring of cyclosporine A in stem cell transplant patients. Steady-state cyclosporine blood concentrations were measured within a dosing interval (12 hours post administration) in 35 allogeneic bone marrow transplant patients receiving 238 mg (±117 mg) twice-daily dose of cyclosporine. Limited sampling strategies were developed by multiple linear regression analysis of relationship between cyclosporine A full AUC(0-12 h) values and different combinations of preselected blood concentrations. Validation of the estimating equations was done by a bootstrap-like cross-validation method. Cross-validation results showed that cyclosporine AUC(0-12 h) could be estimated using either 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision (absolute prediction error of less than 6.2%). The number of estimated area under the drug concentration-time curves within 15% of observed values was greater than 26 (74%) for models used predose concentration with either c(2h) and c(4h) or both. Most of the previously reported single-sample models showed a systematic error in predicting AUC(0-12 h). Although a statistically significant difference in precision of prediction was seen between 3-sample model using c(0), c(2h), and c(4h) and 2-sample models (c(0), c(2h) or c(0), and c(4h)), such a difference (2%) could not be of clinical importance. Other 2-sample estimating equations (models using c(2h) with either c(6h) or c(10h)) with the same degree of precision appear to be less feasible clinically. Cyclosporine AUC(0-12 h) in bone marrow transplant patients could be estimated using 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision.

Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

“…Cyclosporine dose adjustment based on AUC rather than C 0 has consequently become the standard of care. This approach has only just begun to be evaluated in HSCT [10][11][12][13][14][15][16][17][18][19]. Classical determination of AUC entails a large total blood sample volume, high workload to obtain the samples, high assay costs, and potentially a high level of patient inconvenience or distress.…”

Pharmacokinetic tools for the dose adjustment of ciclosporin in haematopoietic stem cell transplant patients

“…Hadjibabaie et al . employed multiple regression analysis (MRA) in 35 patients to estimate CsA AUC using a limited number of samples drawn within the dosing interval . However, limited information about the fit quality was provided and the data given do not show an accurate estimation of the AUC.…”

“…Weighted residuals (WRES) and conditional weighted residuals (CWRES) vs. individual predicted concentrations and histogram of weighted residuals for the three modelling approaches employed multiple regression analysis (MRA) in 35 patients to estimate CsA AUC using a limited number of samples drawn within the dosing interval [19]. However, limited information about the fit quality was provided and the data given do not show an accurate estimation of the AUC.…”

Optical Biosensing in Medical and Clinical Diagnostics

“…In the last couple of years, it has become increasingly evident that improved patient outcome results from pharmacokinetic dosing strategies requiring multiple sampling with the modelling of time-concentration curves. Strategies based on sparse sampling have been developed for clinical purposes estimating the area under the concentration time curve (AUC) and have been shown to substantially improve patient outcome 39,40 . Further substantial progress can be expected from continuous measurement rather than estimation of the AUC.…”