Singh Kapil Dev, Osswald Martin, Ziesenitz Victoria C, Awchi Mo, Usemann Jakob, Imbach Lukas L, Kohler Malcolm, García-Gómez Diego, van den Anker Johannes, Frey Urs, Datta Alexandre N, Sinues Pablo
University Children's Hospital Basel, University of Basel, Basel, Switzerland.
Department of Biomedical Engineering, University of Basel, Basel, Switzerland.
Commun Med (Lond). 2021 Aug 2;1:21. doi: 10.1038/s43856-021-00021-3. eCollection 2021.
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.
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).
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 ( < 0.01) in patients suffering from side effects; (iii) tyrosine metabolism is significantly enriched ( < 0.001), with downregulated pathway compounds in non-responders.
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.
癫痫的治疗管理仍然是一项挑战，因为最佳的全身性抗癫痫药物（ASM）浓度并不总是与改善的临床结果和最小的副作用相关。我们通过同时监测与药物相关和药物调节的代谢物，测试了非侵入性实时呼吸代谢组学作为传统治疗药物监测的扩展用于患者分层的可行性。
这项原理验证性观察性研究涉及对54名儿科患者在2.5年期间进行的93次呼吸测量，以及在两家不同医院对37名成年患者的队列测量。使用二次电喷雾电离-高分辨率质谱（SESI-HRMS）实时测量癫痫患者呼出的呼吸代谢组。
我们表明，可以通过呼吸测试预测全身性ASM浓度。总丙戊酸和游离丙戊酸（VPA，一种ASM）的预测一致性相关系数（CCC）分别为0.63和0.66。我们还发现：（i）VPA代谢在受试者间和受试者内存在高度异质性；（ii）在出现副作用的患者中，几种氨基酸代谢途径显著富集（<0.01）；（iii）酪氨酸代谢显著富集（<0.001），无反应者中该途径的化合物下调。
这些结果表明，对癫痫患者进行实时呼吸分析可提供全身性药物浓度的可靠估计以及药物反应和副作用的风险估计。
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