Tacrolimus

The plasma concentration of tacrolimus is easily affected by many factors, such as race, genetic differences, gender, age, and pathophysiological conditions. Among them, genetic differences are the main cause of individual differences. Tacrolimus is mainly metabolized by the liver in the body, and its plasma concentration is highly related to the activity of human metabolic enzymes. The hepatic drug enzymes CYP3A4 and CYP3A5 are the main enzymes responsible for the demethylation metabolism of tacrolimus in the liver. Among them, the gene polymorphism of CYP3A5 is highly related to heredity, and there are significant ethnic differences, as shown in Table 1. Because CYP3A5 genetic polymorphisms have a significant impact on the plasma concentration of tacrolimus, countries around the world have issued tacrolimus medication guidelines based on pharmacogenomics. Guidelines from the American Clinical Pharmacogenomics Implementation Consortium recommend that patients with CYP3A5 poor metabolizers recommend the use of standard doses of tacrolimus, and the recommended starting dose for patients with extensive and intermediate metabolizers should be increased to 1.5 to 2.0 times the standard dose, and adjust the dosage through therapeutic drug monitoring. In 2011, the Dutch Pharmacogenomics Working Group also pointed out that there is a correlation between the metabolism of tacrolimus and the genetic polymorphism of CYP3A5, but did not give specific recommendations for dose adjustment. The "Technical Guidelines for Gene Detection of Drug Metabolizing Enzymes and Drug Action Targets (Trial)" issued by China in 2015 also clearly emphasized that CYP3A5 plays an important role in the metabolism of tacrolimus, and its reduced activity can lead to increased tacrolimus plasma concentrations and increased adverse reactions. Transplant patients carrying the CYP3A5*3/*3 genotype should reduce the dosage of tacrolimus to avoid adverse drug reactions. The recommended starting dose of tacrolimus based on CYP3A5 genotype in national guidelines is shown in Table 2.

The above guidelines all put forward suggestions for tacrolimus dose adjustment from the perspective of pharmacogenomics, providing a reference for the rational and safe use of tacrolimus in clinical practice. Therapeutic drug monitoring is another important method for detecting the rational use of tacrolimus in clinical practice. Relevant guidelines for tacrolimus therapeutic drug monitoring have also been formulated at home and abroad.

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 Pharmacokinetic characteristics of tacrolimus

The therapeutic window of tacrolimus is narrow, its therapeutic dose is close to the toxic dose, and the pharmacokinetic characteristics and bioavailability of different individuals vary greatly. Therefore, it is necessary to monitor the blood concentration of tacrolimus and adjust the dosage according to the monitoring results, so as to reach the target blood concentration as soon as possible within a certain period of time. Currently, trough concentration (C0) is generally used clinically as a monitoring indicator for tacrolimus therapeutic drugs, and individualized dosage adjustments are made based on it. However, due to large individual differences in the pharmacokinetic characteristics of tacrolimus, the correlation between trough concentration and the area under the concentration-time curve is poor in some cases. The latest research shows that compared with whole blood trough concentrations, the intracellular drug concentrations of calcineurin inhibitors such as tacrolimus and cyclosporine are more closely related to drug efficacy and can be used as monitoring indicators for new therapeutic drugs. However, this view still lacks relevant guidance support. Relevant guidelines at home and abroad provide corresponding suggestions and regulations on the monitoring frequency of tacrolimus blood concentration and the range of target trough concentration. For example, the "KDIGO Clinical Practice Guidelines: Diagnosis and Treatment of Kidney Transplant Recipients" launched by Kidney Disease Improving Global Outcomes (KDIGO) recommends monitoring the plasma drug concentration of tacrolimus in kidney transplant patients who use tacrolimus as an immunosuppressant, and the frequency of monitoring should at least meet the following requirements: Monitor every other day in the short term after transplantation until the target concentration is reached; Changes in drugs or patient conditions that may affect plasma drug concentration should be measured immediately; Decline in renal function indicates nephrotoxicity or rejection should be measured immediately; it is recommended to use the trough concentration 12 hours after taking the drug as a monitoring indicator for tacrolimus therapeutic drugs. In addition, the "Guidelines for the Application of Tacrolimus in Clinical Liver Transplantation" and "Clinical Diagnosis and Treatment Guidelines for Children's Liver Transplantation in China" formulated by the Organ Transplantation Branch of the Chinese Medical Association in 2015, and the "Guidelines for the Application of Tacrolimus in Clinical Kidney Transplantation" formulated in 2010 and the "Guidelines for Immunosuppressive Treatment of Chinese Kidney Transplant Recipients in China" formulated in 2016 both proposed that the frequency of therapeutic drug monitoring should be determined based on clinical needs. At the same time, it is also recommended that the trough concentration 12 hours after administration is used as a monitoring indicator for tacrolimus therapeutic drugs, and it is recommended to draw blood within 0.5 hours before administration. The monitoring frequency and target trough concentration of tacrolimus therapeutic drugs in patients with different organ transplants are shown in Figure 1 and Figure 2.

Comparison item: Tacrolimus (FK506)

Experimental plan: A study to compare the methodology of an imported brand and Diagreat Biotech DF200i to verify the consistency and difference of the Tacrolimus detection kit.

Experimental results: The sample measurement value correlation R²=0.9743 meets the experimental requirements.