Valproic acid levels in neurodevelopmental disorders: correlation with CYP and SULT genes using LC-MS/MS

Area of Science:

• Pharmacogenomics
• Neuropharmacology
• Clinical Chemistry

Background:

• Valproic acid (VPA) is a widely used antiepileptic drug with potential side effects.
• Its use in neurodevelopmental disorders necessitates careful monitoring.
• Genetic factors may influence VPA metabolism and efficacy.

Purpose of the Study:

• To evaluate therapeutic drug monitoring (TDM) for VPA in individuals with neurodevelopmental disorders.
• To investigate the correlation between VPA plasma levels and genetic polymorphisms in CYP and SULT genes.

Main Methods:

• Developed and validated an LC-MS/MS method for VPA quantification.
• Measured VPA plasma levels in 14 patients undergoing VPA therapy.
• Genotyped specific polymorphisms in SULT1A1, CYP2D6, CYP3A5, and CYP2C19 genes.

Main Results:

• Two patients exhibited toxic VPA levels (≥100 µg/mL), one had sub-therapeutic levels (<50 µg/mL).
• Eleven patients had VPA levels within or slightly above the therapeutic range (50-100 µg/mL).
• No significant correlation was found between VPA concentrations and the common genetic variants tested (SULT1A1, CYP2C19*2, CYP2D6*4, CYP2D6*10).

Conclusions:

• VPA therapy in neurodevelopmental disorders is complex, with limited influence from common CYP and SULT gene polymorphisms.
• TDM is essential for optimizing VPA therapy and avoiding toxicity or sub-therapeutic levels.
• Routine pharmacogenetic testing for these specific variants may not be clinically indicated based on current findings.