Therapeutic monitoring of anti-seizure medications in low- and middle-income countries: a systematic review

Background: The treatment gap for epilepsy is large in low- and middle-income countries (LMICs) and the effectiveness and safety of the available anti-seizure medication (ASMs) is not fully understood. We conducted a systematic review to evaluate the extent of therapeutic drug monitoring (TDM) of ASM in LMIC, including purposes and methods used during monitoring. Methods: A search was conducted on four main databases (PubMed, Psych-Info, CINAHL and Embase), with eligible articles screened using a PRISMA checklist and a set of exclusion and inclusion criteria. Full texts were examined to evaluate the extent and practice of TDM in LMICs. Descriptive statistics were used to pool median distribution of TDM across studies. Results: Of the 6,309 articles identified in the initial search, 65 (1.0%) met the eligibility criteria. TDM of ASMs was mostly done to assess toxicity (42.8%), but rarely to monitor adherence (9.0%). TDM differed by economic status and infrastructural status with majority of the studies coming from Europe (53.8%) and upper-middle-income countries (87.6%). First generation ASMs (82.3%) were more likely to be monitored than second generation ASMs (17.6%) and carbamazepine was the most frequently monitored drug. Fluorescence Polarization Immunoassay (FPIA) was the most common technique used for TDM (41.5%) followed by High-Performance Liquid Chromatography (HPLC) (16.9%). In addition, FPIA was the cheapest method of TDM based on approximated costs ($1000, TDx system). Assay validation and quality control were reported variably, and reference ranges used during TDM of ASMs were relatively uniform. Conclusions: TDM is mostly done to evaluate ASM toxicity, but rarely for other reasons such as evaluating adherence or assessing clinical efficacy. There is a need for more investment in comprehensive TDM in LMICs that incorporates dose titration of ASM using pharmacokinetics and pharmacodynamics modelling, for both first generation and second generation ASMs.