Personalised therapeutic management of epileptic patients guided by pathway-driven breath metabolomics

BACKGROUND: Therapeutic management of epilepsy remains a challenge, since optimal systemic antiseizure medication (ASM) concentrations do not always correlate with improved clinical outcome and minimal side effects. We tested the feasibility of noninvasive real-time breath metabolomics as an extension of traditional therapeutic drug monitoring for patient stratification by simultaneously monitoring drug-related and drug-modulated metabolites. METHODS: This proof-of-principle observational study involved 93 breath measurements of 54 paediatric patients monitored over a period of 2.5 years, along with an adult’s cohort of 37 patients measured in two different hospitals. Exhaled breath metabolome of epileptic patients was measured in real time using secondary electrospray ionisation–high-resolution mass spectrometry (SESI–HRMS). RESULTS: We show that systemic ASM concentrations could be predicted by the breath test. Total and free valproic acid (VPA, an ASM) is predicted with concordance correlation coefficient (CCC) of 0.63 and 0.66, respectively. We also find (i) high between- and within-subject heterogeneity in VPA metabolism; (ii) several amino acid metabolic pathways are significantly enriched (p < 0.01) in patients suffering from side effects; (iii) tyrosine metabolism is significantly enriched (p < 0.001), with downregulated pathway compounds in non-responders. CONCLUSIONS: These results show that real-time breath analysis of epileptic patients provides reliable estimations of systemic drug concentrations along with risk estimates for drug response and side effects.