Possibilities of dried blood spots as a matrix in therapeutic drug monitoring of antiepileptic drugs in children

Abstract: For children with epilepsy, therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is essential for treatment. TDM monitoring requires two visits to a health care unit, first for collection of the blood sample before the morning dose and a few days later the family will travel once again to see the pediatrician. For this patient group, blood from a fingerprick, collected on a filter paper at home and sent by mail to the laboratory as a dried blood spot (DBS), could be beneficial and facilitate everyday life. The aim of this thesis has been to investigate whether it is possible to use DBS as a matrix for TDM of common AEDs interchangeably with plasma. A second aim was to study the DBS self-sampling process, to see if guardians of children with epilepsy were able to collect DBS samples with sufficient quality and find what factors influenced a successful collection. Precise and robust liquid chromatography tandem mass spectrometry (LC-MS/MS) methods, using DBS as a matrix, were developed and validated for four major AEDs. The methods met acceptance criteria from the European Medicine’s Agency (Paper I and III). Patient samples were collected from children treated with carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV) and valproic acid (VPA) to perform bridging studies and compare DBS concentrations with plasma. Results concluded that a factor was needed to convert DBS concentrations for CBZ and VPA, to estimated plasma concentrations (Paper II). In the clinical evaluation, only 4 out of 190 comparisons of DBS and plasma concentrations resulted in different dose recommendations The DBS self-collection process was evaluated by comparing the quality of samples obtained from a group of pediatric nurses with a group of guardians to children with epilepsy. Results showed that guardians could collect acceptable quality DBS samples from their children (Paper IV). A mixed method study showed that most of the guardians (80%) found self-sampling at home desirable after a training session. Factors for successful self-sampling were; high motivation, prepared guardians, flexible education with support from a nurse, effective communication between the guardian and the child and that guardians were willing to take on the role as performers (PaperV). The conclusion was that children with epilepsy and their guardians can use DBS as an alternative matrix for self-sampling, and that DBS concentrations of CBZ, LTG and VPA can be analyzed for TDM purposes. DBS for LEV can be collected for compliance queries or for patients where the alternative is no sample at all. These patients are monitored closely and in cases where DBS samples collected at home result in a concentration deviating from the expected or at risk of adverse effects, it is recommended to also collect a plasma sample. Guardians of children with epilepsy are interested in performing self-sampling and by being offered DBS self-collection at home these families can save time and have lower stress levels.

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