Why do different patients have different therapeutic effects after taking the same drug? This involves a drug research direction – pharmacogenomics.
Pharmacogenomics, which mainly studies the influence of genetic factors on drug effects, studies individual differences in drug response from phenotype to genotype. Every gene in the human body has the potential to be mutated and can have a dramatic effect on how a drug works. Pharmacogenomics closely links gene polymorphisms with individual differences in drug effects.
The causes of individual differences in drug response mainly include two aspects: pharmacodynamics and pharmacokinetics. Pharmacodynamics is mainly related to the function of the target or receptor of the drug. The most successful example is the application in the individualized drug delivery of anti-tumor targeted drugs. By detecting the mutation type or biomarker of tumor-related genes, the decision is made. Whether to use targeted therapy drugs, or what kind of targeted therapy drugs to use; and pharmacokinetics are mainly related to the functions of related enzymes and transporters in the process of absorption, distribution, metabolism, and excretion. Once the upstream genes of receptors, metabolic enzymes, and transporters associated with drug action are mutated, drug action can be significantly affected. Therefore, before the patient is administered, by determining the relevant gene mutation type, it is possible to determine the possible changes after the patient takes the drug, adjust the dosing plan, and formulate a personalized dosing plan to improve the efficacy, reduce adverse reactions or toxicity. purpose of the reaction.
According to relevant database records, there are about 200 kinds of metabolic enzyme genes and target gene drugs related to drug safety and efficacy. Clinical studies have been carried out on the genetic changes of various diseases such as cancer. The application of pharmacogenomics to clinical rational drug use makes up for the deficiency of individualized drug administration only based on blood drug concentration, guides and optimizes clinical drug use, and opens up a new way for clinical individualized drug administration.
The application of rational drug use
2.1 Reduce adverse reactions
Patients carrying the human leukocyte antigen-B*1502 (HLA-B*1502) allele and receiving carbamazepine are more likely to develop severe skin reactions such as severe erythema multiforme (SJS) and toxic epidermal necrolysis (TEN). . In China, Thailand, Malaysia, Indonesia, the Philippines and other countries and regions, about 7% to 15% of patients carry the HLA-B*1502 gene, which is much higher than that of European and American populations (2%). – Serious cutaneous adverse reactions associated with mutations in the B*1502 allele. Therefore, before carbamazepine treatment, detecting HLA-B*1502 allele mutation and finding carbamazepine HLA-B*1502-positive individuals can greatly avoid the occurrence of carbamazepine adverse reactions and increase carbamazepine treatment security. The creatine kinase activity of atorvastatin in normal individuals is not related to the A6096G polymorphism of CYP3A5 gene, but for myalgia patients, the creatine kinase activity of CYP3A5 homozygote (GG) individuals is significantly higher than that of heterozygous (AG) individuals, revealing that carriers of CYP3A5 Homozygous individuals who take atorvastatin are more prone to muscle damage. Therefore, during clinical treatment, doctors can adjust the dose of atorvastatin according to the patient’s CYP3A5 genotype to avoid adverse reactions such as muscle damage.
2.2 Determining the dose
Due to the narrow therapeutic window of warfarin, its efficacy can vary by up to 20 times among different individuals, thus greatly limiting its clinical application. CYP2C9*3 and VKORC1C-1639T are two gene-related loci of warfarin. Warfarin is mainly metabolized by CYP2C9. The mutation of this gene can lead to the accumulation of warfarin in the body. Therefore, patients with this genotype mutation take warfarin. The dose of farin should be reduced; VKORC1 is the target of warfarin, and patients with this gene mutation have increased sensitivity to warfarin, so patients with VKORC1 gene mutation should reduce the dose of warfarin. Therefore, using relevant technologies to detect whether the CYP2C9*3 and VKORC1C-1639T gene loci of patients are mutated and using formulas to calculate the most suitable dose of warfarin can reduce the incidence of adverse reactions of warfarin; at the same time, male, female, Factors such as obesity and taking amiodarone can also affect the body’s absorption and metabolism of warfarin. The establishment of the warfarin individualized medication model has greatly promoted the application of clinical pharmacogenomics to clinical transformation, and is a milestone progress in clinical pharmacogenomics research.
Clopidogrel is a prodrug, which is mainly metabolized by CYP2C19 into active products to exert its therapeutic effect. The CYP2C19 gene mutants have different effects on the pharmacokinetics and pharmacodynamics of clopidogrel. Some variants can make the drug less effective, while others can increase the risk of bleeding. In addition, clopidogrel is mainly absorbed through the intestinal tract, and the multidrug resistance gene ABCB1 has a certain influence on the absorption process. Therefore, by measuring the mutation of clopidogrel-related genes, while detecting the speed of CYP2C19 metabolism, we can also detect the absorption of clopidogrel in the intestine by detecting the ABCB1 gene, and then evaluate the clinical application of clopidogrel. risk, guide dosage adjustment, and reduce the incidence of cardiovascular adverse events. CYP2C19*2 and CYP2C19*3 are two common mutant alleles. The frequency of CYP2C19*2 in Asians is 25%, which is higher than 13% in Caucasians, while CYP2C19*3 occurs in Asians The frequency is 8%, far greater than the less than 1% of Caucasians.
2.3 Selection of targeted agents
Tumor molecule-targeted drugs are designed to attack specific target molecules, so it is necessary to detect whether there is a corresponding target in the patient before taking the drug to exert its curative effect. The launch of the first breast cancer molecular targeting agent trastuzumab has greatly promoted the research of molecular targeted drugs, and also promoted the development of clinical pharmacogenomics and individualized therapy. In patients with HER2-positive breast cancer, trastuzumab was more effective than in patients with HER2-negative breast cancer. Further research also found that trastuzumab was also effective in HER2-positive gastric cancer patients. Trastuzumab was approved by the FDA in 2010 for the treatment of patients with HER2-positive gastric cancer. Gefitinib is the first small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, which binds to the intracellular kinase domain of EGFR to inhibit the activity of tyrosine kinase and exert an anti-tumor effect. A randomized controlled study (Iressa Pan-Asia Study, IPASS) showed that gefitinib was more effective in non-smoking/light smoking patients with lung adenocarcinoma in Asian population. The proportion of EGFR mutations in lung adenocarcinoma patients is higher, in patients with EGFR gene exon 19 deletion, exon 21 mutation (L858R) and exon 18 mutation (G719X), the use of small molecule casein Aminokinase inhibitors are more effective. The IPASS research results not only ushered in the era of targeted therapy for non-small cell lung cancer, but also suggested racial differences in the use of small molecule targeted agents. At present, the tumor molecular targeted drugs used in the Chinese population mainly include small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, anti-EGFR monoclonal antibodies, anti-HER-2 monoclonal antibodies, BCR-ABL Tyrosine kinase inhibitors, ALK kinase inhibitors, etc.
In summary, with the rapid development of genetic analysis technologies, such as sensitive and rapid high-throughput genetic testing technology, more and more relationships between individual differences in the in vivo disposition process of drug effects and gene polymorphisms have been elucidated. It makes it possible to apply molecular diagnostic technology to accurately select drugs and doses, and enables the development of new drugs based on pharmacogenomics.