Valproate, also known as Valproate Sodium or Valproate Magnesium, is a widely used antiepileptic drug that is also used to treat bipolar disorder and prevent migraines. Valproate exerts its antiepileptic effects through several mechanisms ^[1]. It increases the synthesis and release of gamma-aminobutyric acid (GABA) and inhibits the degradation of GABA, which enhances the inhibitory neurotransmission of GABA^[2]. In addition, it blocks voltage-dependent sodium channels, reducing neuronal hyperexcitability and decreasing the frequency and intensity of seizures^[2].

Valproic acid faces many challenges in its clinical application, mainly in the following areas ^[3]:

Valproic acid can cause severe liver damage, with a higher risk of liver failure, especially in children (<2 years of age) and in patients with inherited mitochondrial disorders such as Alpers syndrome. In addition, valproic acid can cause pancreatitis, a potentially life-threatening inflammatory condition that manifests itself as epigastric pain, nausea, and vomiting. Hyperammonemia: Valproic acid can cause elevated levels of ammonia in the blood, which can lead to hyperammonemic encephalopathy, which manifests as mental retardation and impaired consciousness, and can lead to coma or even death if not treated promptly. Risk factors include concomitant topiramate use, urea cycle disorders, mental retardation, and carnitine deficiency. Hematologic abnormalities: Valproic acid may cause thrombocytopenia (a significant decrease in platelet count), increasing the risk of bleeding. Neurological adverse reactions: Valproic acid may cause patients to experience mental behavioral abnormalities such as anxiety, depression, and suicidal thoughts, as well as neurological symptoms such as dizziness, drowsiness, and ataxia. Other side effects: include alopecia, weight gain, and vision changes (e.g., double vision or blurred vision).

Antiepileptic drugs: such as phenobarbital, phenytoin sodium and other hepatic enzyme inducers in combination, can accelerate the metabolism of valproic acid and reduce its blood concentration; carbamazepine in combination with a weaker interaction, but still need to monitor blood concentrations. Anticoagulant drugs: such as warfarin, valproic acid can enhance its anticoagulant effect and increase the risk of bleeding. With psychotropic drugs: such as lithium salts, valproic acid can increase the blood concentration of lithium salts, enhance its toxicity; antidepressant drugs in combination, need to be vigilant about drug-drug interactions, such as increasing the central nervous system inhibition. Topiramate: combination may increase the risk of hyperammonemia.

Pregnant Women: Valproic acid use during pregnancy can significantly increase the risk of fetal birth defects, such as neural tube defects and cardiac malformations. In addition, it may affect the cognitive development of children. Therefore, valproic acid is not recommended for migraine prevention during pregnancy unless necessary. Nursing women: Valproic acid can be secreted through breast milk and should be used with caution and weigh the pros and cons in nursing women. Children: Special attention should be paid to the risks of hepatotoxicity and hyperammonemia when valproic acid is used in children.

1. Ensuring drug efficacy

Determine the effective blood concentration range: Valproic acid has an effective blood concentration range of 50 - 100 μg/ml. with TDM, it is possible to ensure that the patient's blood concentration reaches this effective range, thus effectively controlling seizures, stabilizing the mood of patients with bipolar disorder, or preventing migraine attacks. If the blood concentration is too low, the desired therapeutic effect may not be achieved, leading to recurrence or exacerbation of the condition.

Individualized Dosage Adjustment: The metabolism rate of drugs varies from patient to patient, and even if the same dosage is given, the blood concentration may be different. TDM can help doctors adjust the dosage of drugs according to the individual patient's blood concentration, so that each patient can get the best therapeutic effect.

2. Reduce adverse reactions

Avoiding toxic blood levels: excessive blood levels of valproic acid may lead to serious adverse reactions such as hepatotoxicity, hyperammonemia, and central nervous system depression. With TDM, excessive blood levels can be detected in time and appropriate measures (e.g., dose reduction, suspension of medication, etc.) can be taken to reduce the risk of adverse reactions.

Early Detection of Potential Problems: TDM can detect abnormal blood levels in advance, before patients experience significant adverse effects, enabling physicians to adjust treatment regimens in a timely manner to avoid further development of adverse effects.

3. Improve drug safety

Monitoring of special populations: For special populations, such as children, the elderly, patients with hepatic insufficiency, and pregnant women, the metabolism and excretion of valproic acid may be affected, and its blood concentration is more prone to abnormality. TDM can provide more accurate monitoring of the use of medication for these special populations to ensure the safety of the medication.

Drug interaction monitoring: Valproic acid has multiple interactions with other drugs that may affect its blood levels. Through TDM, the effect of drug interactions on blood levels can be detected in time, so that the drug dose can be adjusted or other drugs can be replaced to avoid the risk of potential drug interactions.

4. Optimization of treatment protocols

Evaluating the effectiveness of treatment: TDM not only monitors blood levels, but also evaluates the effectiveness and safety of the treatment regimen in conjunction with the patient's clinical signs and symptoms. If the blood concentration is within the effective range but the patient's condition is still not under control, it may be necessary to consider other therapeutic options or combinations of drugs.

Guiding long-term treatment: For patients who need to use valproic acid for a long period of time, TDM can help doctors regularly assess the patient's treatment, promptly identify potential problems, and adjust the long-term treatment plan according to the patient's condition changes and blood concentration, to ensure the continued effectiveness and safety of the treatment.

Bibliography:

1. Hinderling PH, Hartmann D. Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans. Ther Drug Monit. 1991;13:381–401. doi: 10.1097/00007691-199109000-00001。

2. Patocka J, Nepovimova E, Wu W, Kuca K. Digoxin: pharmacology and toxicology—a review. Environ Toxicol Pharmacol. 2020;79:103400. doi: 10.1016/j.etap.2020.103400。

3. Gault H, Longerich L, Dawe M, Fine A. Digoxin-rifampin interaction. Clin Pharmacol Ther. 1984;35:750–754. doi: 10.1038/clpt.1984.106。