What are the key points about clinical voriconazole therapeutic drug monitoring?

In 2020, the American Thoracic Society put forward the 5R principles for the effective definition of antibiotic management, that is, 'use the right antibiotic at the right time, use the right dose and the right course of treatment for the right pathogen', which can help clinically optimize the treatment of antibiotics. Antibacterial drugs are commonly used drugs in patients with severe infections, and therapeutic drug monitoring (TDM) can help optimize drug doses and achieve individualized treatment. Therefore, how to guide the individualized use of antibacterial drugs through TDM is a hot issue currently concerned.

In the past, the main goal of TDM was to prevent drug toxicity, and antibacterial drugs that generally require TDM usually have a narrow therapeutic index. For example, vancomycin has a narrow therapeutic window, and previous studies have shown that therapeutic drug monitoring for it can reduce the risk of nephrotoxicity and improve the efficacy of treatment. Recently, the clinical demand for TDM has changed from the traditional prevention of toxicity to the maximum optimization of clinical treatment outcomes. For example, when voriconazole is used to treat patients with invasive fungal infections, TDM can effectively optimize the concentration, avoid treatment failure, and reduce the risk of drug resistance. However, there are still many issues to be discussed in the implementation of TDM of voriconazole.

 1. Introduction to voriconazole

Voriconazole is a broad-spectrum second-generation triazole antifungal drug. It is the first-line treatment drug for the treatment of invasive aspergillosis and Candida krusei infection, and is widely used in the treatment and prevention of various invasive fungal diseases. The metabolism of voriconazole in vivo is affected by genetic polymorphisms of metabolic enzymes, drug interactions, liver insufficiency, age and other factors, and the steady-state trough concentration of voriconazole is significantly related to its curative effect and side effects (liver damage, nerve damage, etc.). Therefore, the 'Guidelines for Individualized Medication of Voriconazole in China' recommends that voriconazole therapeutic drug monitoring should be carried out to ensure the effectiveness and safety of voriconazole use.

2、Necessity of voriconazole blood concentration monitoring

Voriconazole is mainly metabolized by the liver. Studies have shown that patients' age, body weight, CYP2C19 gene polymorphism, drug interactions, liver insufficiency and other important factors will seriously affect the blood concentration of voriconazole, which makes the individual differences of voriconazole in different populations very large. In addition, the therapeutic effect of voriconazole is closely related to the blood drug concentration. As high as 56% of the patients, the trough concentration of voriconazole was lower than or exceeded the safety threshold range, which directly led to the failure of clinical treatment or the increase of adverse reactions such as abnormal liver function, cardiotoxicity, vision changes or visual disturbances, etc.

3、Who needs voriconazole therapeutic drug monitoring?

Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society recommends voriconazole plasma concentration monitoring for the following people:

Strong recommendation:

Patients with liver insufficiency.

Patients who are co-administered with drugs affecting voriconazole.

Patients with CYP P450 2C19 gene mutation.

Patients with toxicity or poor efficacy.

Life-threatening patients with severe infections.

Weak recommendation: voriconazole blood concentration monitoring in other patients except the above.

(Note: 1. Compared with adults, children have higher clearance rate and larger volume of distribution, and lower oral bioavailability, resulting in lower peak and trough values. According to the routine dosage of adults, it will reduce efficacy and increase the risk of treatment failure in children. Therefore, it is recommended to adjust the dosage of children patients according to TDM. 2. Drugs that affect the plasma concentration of voriconazole: CYP2C19, CYP2C9and CYP3A4 inhibitors or inducers such as rifampicin, carbamazepine, omeprazole, macrolide antibiotics, tacrolimus, cyclosporine, sirolimus, etc.)

4、？When should voriconazole therapeutic drug monitoring be performed?

1. When giving a loading dose, it is recommended that the timing of the first monitoring of voriconazole should be no earlier than before the fifth dose (steady-state trough concentration).

2. When the dose of voriconazole is adjusted, adverse events or poor curative effect occur in patients, and drugs that affect the pharmacokinetics of voriconazole are added or discontinued, it is recommended to repeatedly monitor the steady-state trough concentration of voriconazole.

5、Target steady-state trough concentration range of voriconazole

The recommended target steady-state trough concentration range for voriconazole is 1.0-5.0 ug/mL.

6、伏立康唑给药剂量调整方案   Voriconazole dosage adjustment plan

7、Voriconazole dose reduction or withdrawal indications

(1) Indications for dose reduction

① Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeds 3 times the upper limit.

② Alkaline phosphatase (ALP) or glutamyl transpeptidase (GGT) exceeds 2.5 times the upper limit.

③ Total bilirubin (T-Bil) exceeds 1.5 times the upper limit.

④ Moderate neurological/mental impairment or visual impairment, limited use of tools in daily life.

⑤ The rash area exceeds 10%, and oral medication is required, and the use of tools in daily life is limited.

(2) Indications for drug withdrawal

① Any one of alanine aminotransferase (ALT) / aspartate aminotransferase (AST) / alkaline phosphatase (ALP) / glutamyl transpeptidase (GGT) exceeds 5 times the upper limit.

② Total bilirubin (T-Bil) exceeds 3 times the upper limit.

③ Severe neurological/mental impairment or visual impairment, limited self-care in daily life.

④ The rash area exceeds 30% of the body surface area, and the self-care in daily life is limited or sleep is affected. Oral corticosteroids or anti-inflammatory drugs are required.

8、 Voriconazole drug interactions