Martial Lisa C, Hoogtanders Karin E J, Schreuder Michiel F, Cornelissen Elisabeth A, van der Heijden Jac, Joore Manuela A, Van Maarseveen Erik M, Burger David M, Croes Sander, Brüggemann Roger J M, Aarnoutse Rob E
*Department of Pharmacy, Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands. Dr. Martial is now with the Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands; †Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, Maastricht, the Netherlands; ‡Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, the Netherlands; §Dried Blood Spot Laboratory (DBSL), Geleen, the Netherlands; ¶Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Center, Maastricht, the Netherlands; ‖Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands; and **CAPHRI-School for Public Health and Primary Care, Maastricht University Medical Center, Maastricht, The Netherlands.
Ther Drug Monit. 2017 Aug;39(4):412-421. doi: 10.1097/FTD.0000000000000422.
Tacrolimus and mycophenolic acid (MPA) are the backbone of immunosuppressive therapy after pediatric kidney transplantation. Dosing of these drugs is individualized by therapeutic drug monitoring. Dried blood spot (DBS) sampling may prove beneficial over conventional venous sampling. We aimed to develop and clinically validate a DBS method for tacrolimus and MPA in children.
A joint DBS liquid chromatography-mass spectrometry assay for tacrolimus and MPA was developed. DBS-specific items included the hematocrit effect and influence of spot volume. Subsequently, a clinical validation study among children aged 2-18 years was performed to assess the agreement between observed and DBS-predicted venous concentrations. Agreement of the methods was assessed with Passing-Bablok regression, Bland-Altman plots, and quantification of the DBS predictive performance in terms of bias (median percentage prediction error) and precision (median absolute percentage prediction error), both should be <15%.
A total of 40 tacrolimus and 32 MPA samples were available from 28 children. Conversion factors were used to predict venous concentrations from DBS. For tacrolimus, 95% of the individual ratios of predicted and observed concentrations were within a range of 0.74-1.28, with 85% of these ratios between 0.80 and 1.20 (Bland-Altman plots). For MPA, the 95% limits of agreement represented a broader range of 0.49-1.49%, and 72% of individual ratios were between the 0.80 and 1.20 limits. Median percentage prediction error and median absolute percentage prediction error were less than 15% for both drugs.
A DBS assay was developed for tacrolimus and MPA. Tacrolimus venous concentrations could be adequately predicted from DBS. DBS analysis of MPA seemed to be a semiquantitative measurement at the most when compared with conventional plasma analysis, considering the high variability between observed and predicted concentrations. Next, home-based DBS sampling of tacrolimus for the purpose of therapeutic drug monitoring will be implemented into routine clinical care.
他克莫司和霉酚酸（MPA）是小儿肾移植后免疫抑制治疗的基础药物。这些药物的剂量通过治疗药物监测进行个体化调整。与传统静脉采血相比，干血斑（DBS）采样可能具有优势。我们旨在开发并在临床上验证一种针对儿童他克莫司和MPA的DBS检测方法。
开发了一种用于他克莫司和MPA的联合DBS液相色谱 - 质谱分析法。DBS特有的因素包括血细胞比容效应和血斑体积的影响。随后，对2至18岁的儿童进行了一项临床验证研究，以评估观察到的静脉浓度与DBS预测的静脉浓度之间的一致性。采用Passing - Bablok回归、Bland - Altman图以及根据偏差（中位百分比预测误差）和精密度（中位绝对百分比预测误差）对DBS预测性能进行量化来评估方法的一致性，两者均应<15%。
共从28名儿童中获取了40份他克莫司样本和32份MPA样本。使用转换因子从DBS预测静脉浓度。对于他克莫司，预测浓度与观察浓度的个体比值中，95%在0.74 - 1.28范围内，其中85%的比值在0.80至1.20之间（Bland - Altman图）。对于MPA，一致性的95%界限范围更宽，为0.49 - 1.49%，72%的个体比值在0.80至1.20界限之间。两种药物的中位百分比预测误差和中位绝对百分比预测误差均小于15%。
开发了一种用于他克莫司和MPA的DBS检测方法。可以从DBS充分预测他克莫司的静脉浓度。与传统血浆分析相比，考虑到观察浓度与预测浓度之间的高变异性，MPA的DBS分析最多似乎是一种半定量测量。接下来，用于治疗药物监测的他克莫司家庭DBS采样将纳入常规临床护理。
