Pharmacogenetics-Informed Pharmacometabolomics as an Innovative Approach to Assessing the Safety and Risk of Pharmacotherapy with Valproic Acid

Abstract

Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs.Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice.Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles.Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.

Ethnic Aspects of Valproic Acid P-Oxidation

“…Pharmacogenetically informed pharmacometabolomics is a new approach that allows individual prediction of the risk of impaired VPA P-oxidation, increased levels of active toxic VPA metabolites in biological fluids (blood, urine, saliva, etc.) based on unchanged PGx results, and an optimized selection and volume of metabolic studies (TDM and gas-liquid chromatography/mass spectrometry) [114]. In addition, it is promising and important in the future to compare the results of pharmacogenomic and pharmacometabolic studies of the therapeutic and toxic metabolites of VPA in order to identify allelic variants that contribute to metabolomic variations in different populations involving the frequencies of low-functioning and non-functional alleles of CYP family genes that are not influenced by the therapeutic response to valproate [1] in various ethnic and racial groups in the world population.…”

“…The prescription of VPA is possible for patients with the IM phenotype, but the dosage of valproate should be reduced by an average of 25% of the average therapeutic one. At the same time, it is not recommended to additionally prescribe other drugs with a similar pathway of P-oxidation in the liver and/or drugs that are inhibitors of low-functioning CYPs in a particular patient [114]. In 2011, a personalized approach to pharmacotherapy, called pharmacometabolicinformed pharmacogenomics, was proposed, which aims to identify metabolic biomarkers as a result of treatment [115].…”