Limited sampling strategy for prolonged-release tacrolimus in renal transplant patients by use of the dried blood spot technique

Abstract

PurposeThe aim of this study was to develop a clinically applicable limited sampling strategy for ambulatory Caucasian kidney transplant patients to estimate area under the curve in a 24-h period (AUC0–24) of prolonged-release tacrolimus.MethodsTwenty six kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus, were enrolled. In each patient, seven blood samples were collected during a period of 24 h by use of the validated dried blood spot method. Best subset selection multiple linear regression was performed to derive limited sampling strategy (LSS). The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted.ResultsThe prediction formula for the AUC0–24 using the time points 0, 2, and 4 h after ingestion (C0h-C2h-C4h) provided the highest correlation with the AUC0–24 (r2 = 0.95): AUC0–24 = 44.9 + 8.9 × C0h + 2.1 × C2h + 7.6 × C4h. Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8 %, respectively. For the same patients, the correlation between C24h and AUC0–24 was worse (r2 = 0.77) while MPPE and MAPE were 6.2 and 7.2 %, respectively.ConclusionIn the outpatient department, a LSS using C0h-C2h-C4h can be used for reliable estimation of the AUC0–24 of prolonged-release tacrolimus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1863-6) contains supplementary material, which is available to authorized users.

Limited sampling strategy to predict the area under the curve of tacrolimus in Mexican renal transplant pediatric patients receiving Prograf® or non‐innovator formulations

“…The acceptable percentage limits for MPE, MAE, and RSME were >5%, 10%, and 15%, respectively. In accordance with van Boekel et al and Niioka et al, we considered these criteria acceptable due to the narrow therapeutic index of tacrolimus in which small changes in exposure could be clinically relevant. More recently, Vadcharavivad and coworkers used the same criteria to validate the Wong et al's .…”

“…AUC estimation using an LSS could be performed by multiple linear regression or by Bayesian estimation with population PK models. Several LSS have been developed for the estimation of tacrolimus AUC in adult kidney transplant recipients, most of them including 2‐5 sampling time points for the estimation of the AUC . Wong and coworkers developed a LSS for adult kidney transplant patients .…”

Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?

“…Specifically for drugs that exhibit a narrow therapeutic window requiring close monitoring, Bayesian estimators based on population pharmacokinetic models can be developed to project the individual drug exposure from sparse feedback measurements of drug concentration and limited sampling strategies. 89,90 These approaches developed for tacrolimus have been reviewed by Brooks et al 20 The authors highlighted the potential for Bayesian forecasting dosage prediction to achieve AUC targets and providing the benefits on individual outcomes compared to current therapeutic drug monitoring based on trough concentrations only. However, further research is still required to determine the most appropriate population model with relevant covariates for tacrolimus.…”

Clinical application of a dried blood spot assay for sirolimus and everolimus in transplant patients

“…Traditionally, venous blood samples are used for monitoring of immunosuppressive drug concentrations and patients have to travel to the hospital on a regular basis to have their blood drawn. To decrease the burden for patients, dried blood spot (DBS) home sampling has been developed among various micro sampling methods for several drugs, including immunosuppressants, to enable home sampling [5][6][7][8][9][10][11][12][13][14][15][16]. For this, a drop of blood from a fingerprick is applied to a sampling card and dried.…”

“…Therefore, a clinical validation study showing interchangeability between DBS and venous sampling is required before clinical application [18]. This is shown for tacrolimus, cyclosporin A and creatinine [5,[7][8][9][10][11][12][13][14][15]19]. For sirolimus, Dickerson et al report agreement between fingerprick DBS and venous samples in 25 pediatric transplant patients, where mean DBS concentrations were on average 0.8 μg/L lower than venous samples [15].…”