Dried Blood Microsampling-Based Therapeutic Drug Monitoring of Antiepileptic Drugs in Children With Nodding Syndrome and Epilepsy in Uganda and the Democratic Republic of the Congo

Abstract

Nodding syndrome is a highly debilitating, generalized seizure disorder, affecting children in subregions of sub-Saharan Africa. Despite many efforts towards finding its etiology, the exact cause of the syndrome still remains obscure. Therefore, to date, patients only receive a symptomatic care, including the administration of first-generation anti-epileptic drugs (AEDs) for seizure control. Since information about medication effectiveness within this population is completely lacking, the aim of this study was to perform therapeutic drug monitoring (TDM) to seek whether an answer could be provided to the question why for some patients the symptoms decrease, whilst in others the epileptic seizures remain poorly controlled. Seeing the challenging context in which sampling needed to take place (remote areas, devoid of electricity, running water, etc.), dried blood matrices (i.e. dried blood spots (DBS) and volumetric absorptive microsampling (VAMS) devices) were considered fit-for-purpose.Seeing the similarities between the syndrome and other forms of epilepsy, also samples originating from patients suffering from (onchocerciasis-associated) epilepsy were included.In total, 68 patients with Nodding syndrome from Uganda, 58 Ugandan patients with epilepsy and 137 patients with onchocerciasis-associated epilepsy from the Democratic Republic of the Congo (DRC) were included in this study. VAMS samples and DBS were analyzed using fully validated methods, involving manual extraction or fully automated extraction, respectively, prior to quantification using liquid chromatography coupled to tandem mass spectrometry.Analysis revealed that serum concentrations (calculated from DBS) within the respective reference ranges were attained for only 52.9% of the 68 Nodding syndrome patients treated with valproic acid, for 21.4% of the 56 Ugandan epilepsy patients treated with carbamazepine, and for 65.7% of the 137 onchocerciasis-associated epilepsy patients from the DRC treated with phenobarbital. In all other instances, concentrations were subtherapeutic. Furthermore, when comparing DBS to VAMS concentrations, an inexplicable overestimation was observed in the latter. Finally, no obvious link could be observed between the obtained drug concentrations and the amount of seizures experienced during the last month before sampling, disclosing the fact that the level of improvement of some patients cannot simply linked to reaching therapeutic concentrations.

Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age

“…To date, VAMS is still a novel microsampling method and is not yet routinely used in neonates. Since first data published in 2014 [40], several drugs have been monitored through VAMS such as antiepileptics, anthelmintic and immunosuppressants [41][42][43][44]. VAMS can be utilized to collect blood samples from a single finger or heel prick, allowing to obtain accurate volumes, without hematocrit's influence.…”

Therapeutic Drug Monitoring of Antiseizure Medications Using Volumetric Absorptive Microsampling: Where Are We?

“…Moreover, after one month, there was a worsening of stability for VPA at all temperatures. Changes in the stability of PB and CBZ-E were also reported at 60 • C. In another study, Velghe and colleagues [26] went one-step further, testing clinical samples collected in Uganda that were mailed to laboratories in Belgium and finally stored −20 • C. To assess stability, QC samples, stored at −20 • C, in zip-closure plastic bags containing desiccant gel, were examined after storage times ranging from 4 days to 31 days. QC samples with nine leftover hospital patient samples were also examined after 93 and 186 further days of storage.…”

“…The pharmaceutical treatment in patients with Nodding syndrome mainly include the first-generation antiseizure medications such as VPA, CBZ, PHT, and PB. The VAMS ® procedure reported by Velghe et al [26] involved the sample collection in the morning by mean of finger pricking, immediately before the first medication of the day. The samples once dried (approximately 2 h) were stored at −20 • C. The Mitra ® samples were then extracted in 100 µL of acetonitrile/water (80:20, v/v) mixture, containing 5 mM ammonium acetate and deuterated internal standard.…”

“…It was observed that even when high HCT values seem to correspond to a lower recovery, there are not statistically significant differences between the different HCTs, except for the recovery of VPA at 62% HCT compared to 42% in samples prepared by pipetting 10 µL onto the samplers. In the more recent study, Velghe et al [26] excluded HCT effect on the observed median HCT level of 38.1% (range 20.9-47.9%) of their patients (data shown in Supplemental Digital Content 1, http://links.lww.com/TDM/A381 (accessed on 10 February 2021).…”

“…To date, studies involving actual sampling from the finger are still rare. Among those analyzed in this review, only two studies make use of finger pricking or capillary blood for ASMs [ 24 , 26 ]. In 2019, Sciberras et al [ 27 ] published a pharmacokinetic study of radiprodil oral suspension in healthy adults comparing conventional venous blood sampling with two microsampling techniques, comprising VAMS ® technology.…”