Scenario 1: There is a drug with narrow therapeutic windows, toxic at high doses and ineffective at low doses. How could we accurately determine the dosage?

Scenario 2: The same dose of medicine in different patients suffering from the same disease has different effects, some respond well while others barely respond, some have no or mild adverse reaction while others show toxicity, and severe cases are even life-threatening. How can individualized precision medicine be achieved?

Tacrolimus is mainly used for organ transplantation, skin diseases, atopic dermatitis, psoriasis, vitiligo, and autoimmune diseases (lupus nephritis, systemic lupus erythematosus, etc.). Due to the narrow therapeutic window, the same dose of tacrolimus will result in different blood drug concentrations in different patients due to individual differences. Therefore, we must pay attention to the monitoring of tacrolimus blood drug concentration, and adjust the dosage accordingly, so as to reach the effective blood drug concentration within a certain timeframe, and at the same time avoid toxic concentration, which will lead to liver and kidney function deterioration, nausea, vomiting, hyperglycemia, and other adverse reactions.

Cyclosporine A is a new type of immunosuppressive drug, which is often used to prevent rejection after organ transplantation (liver, kidney, heart, bone marrow, etc.) and treatment of autoimmune diseases (systemic lupus erythematosus, atopic dermatitis, nephrotic syndrome, etc.). Detection of its blood concentration has important clinical significance for improving the success rate of transplantation, preventing side effects (diabetes, kidney damage, neurotoxicity, gastrointestinal symptoms, hypertension, infection, tumor, etc.), and improving curative effect.

Mycophenolic acid is an immunosuppressant with a strong immunosuppressive effect and low liver and kidney toxicity. It is clinically widely used to prevent organ rejection post kidney, liver, heart, and other organ transplantation, improve the survival rate of patients and improve the quality of life of patients. Its clinically effective therapeutic window is narrow. Insufficient dosage of immunosuppressant will lead to organ rejection after transplantation while excessive use will cause various toxic side effects in the gastrointestinal system, hematopoietic system, and may lead to infection. At the same time, due to the various adverse reactions, large amounts of different factors affecting drug metabolism, individual differences in metabolizing abilities for drug metabolism, and more inter-individual and intra-individual variations, there are many differences in blood drug concentrations even with the same dose. Monitoring the blood concentration of the drug is used to formulate an individual immunosuppressant treatment plan, which can avoid toxic side effects and acute rejection.

Carbamazepine is the drug of choice for the treatment of simple and complex focal seizures, and can also be used for the treatment of peripheral neuralgia, neurogenic diabetes insipidus, prevention or treatment of manic depression, and antagonize digoxin poisoning-caused arrhythmia. Its therapeutic range is narrow: 4-12 μg/mL, the range of effective blood drug concentration is narrow, individual differences are large, and the adverse reactions are mainly in the nervous system and gastrointestinal system. It is often difficult for clinicians to effectively control epilepsy with the dosage of medication determined based on experience alone. Blood drug concentration testing is helpful for clinicians to design individualized drug regimens for patients, to ensure the safety of the patient by reducing adverse effects.

Valproic acid is a broad-spectrum anti-epileptic drug. It is the first-line treatment of epilepsy syndrome grand mal seizures, absence seizures, myoclonic seizures and various types of petit mal seizures, limited seizures, mixed epilepsy, and febrile convulsions, etc., as well as for reduing or preventing manic episodes in bipolar disorder. However, its therapeutic range is narrow: 50-100 μg/mL. Adverse reactions include central nervous system depression, fatal liver toxicity, etc. There are large individual differences in drug metabolism. The blood drug concentration is more correlated with the drug effect than the dose given. Many factors that affect the drug deposition of valproic acid. Monitoring blood drug concentration is conducive to rational drug use.

Phenytoin is used to treat grand mal seizures, trigeminal neuralgia, manic depression, etc. At the same time, it is suitable for certain types of arrhythmias, especially ventricular and supraventricular arrhythmias caused by digitalis poisoning. However, the therapeutic range is narrow: 10-20 μg/mL, with large individual differences, and severe adverse reactions, with neurotoxicity being the most common adverse reaction. In order to improve the safety and effectiveness of clinical use, phenytoin is included in the routine therapeutic drug monitoring (TDM) program.

Vancomycin has a narrow therapeutic window, undergoes complex metabolism, and is highly variable in therapeutic response. Many different factors and pathophysiological conditions may affect the concentration of vancomycin within the body. Insufficient doses of vancomycin may affect the drug’s efficacy and may even lead to drug resistance. Excessive concentrations increase the probability of nephrotoxicity and ototoxicity. Especially in the case of patients taking aminoglycoside antibiotics, administration of large doses of vancomycin, patients with renal insufficiency, etc., monitoring the blood concentration of vancomycin is of great significance. The concentration monitoring results can be combined with the patient's clinical symptoms and related laboratory tests to design individualized treatments for patients, select appropriate doses, and reduce the occurrence of bacterial drug resistance and adverse reactions.

Methotrexate is an antifolate anti-neoplastic drug, which mainly inhibits the synthesis of tumor cells by inhibiting dihydrofolate reductase, thereby inhibiting the growth and replication of tumor cells. It has a highly effective on a variety of malignant tumors, such as non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, osteosarcoma, and head and neck malignant tumors. However, methotrexate has many adverse effects and there are a lot of individual differences in drug distribution. Therefore, the blood concentration of methotrexate should be monitored for adverse reactions so, rescue treatment and treatment of symptoms could be carried out in time until the blood concentration is lower than 0.05- 0.1 uM. This can effectively improve the drug effect and avoid serious side effects.

Digoxin is a form of digitalis commonly used in clinical settings, mainly for congestive heart failure, atrial fibrillation, atrial flutter, paroxysmal tachycardia, and premature ventricular contraction. Digoxin has a short time of onset and a long half-life within the body. The therapeutic dose is near the toxic dose with serious adverse reaction. The common clinical manifestations of digoxin poisoning include gastrointestinal symptoms, neuropsychiatric symptoms, and arrhythmia. Factors related to digoxin poisoning include age, gender, drug dose, electrolyte level, renal function, and combined drug use. Therefore, it is critical to monitor its blood concentration during clinical practice to adjust the drug dose accordingly. Application of individualized therapy plan increases rationalized application of digoxin and lowers or prevents the incidence of toxicity.

Theophylline is metabolized by the cytochrome P450 microsomal enzyme system in the liver. When used in combination with drugs that inhibits or potentiates enzymes within this system, the blood drug concentration will change and needs to be monitored at all times. The incidence of adverse reactions to theophylline is closely related to the blood concentration. The pharmacological effect of theophylline is directly proportional to the blood concentration in the range of 5-20 mg/L. So the therapeutic window of theophylline is narrow and the effective concentration is close to the toxic concentration. Moreover, the bioavailability and the elimination rate of theophylline varies greatly among individuals and the blood concentration of different patients given the same dose varies greatly. In order to ensure the safe and effective clinical application of theophylline and adjust the dose in time, an important clinical method is to monitor drug concentrations.

Voriconazole is a new type of triazole broad-spectrum antifungal drug. It is an inhibitor of ergosterol biosynthesis. It mainly exerts antifungal effects by destroying fungal cell membranes and preventing fungal growth. It has good antibacterial activity mainly against acute invasive Aspergillus, severe fluconazole-resistant invasive Candida, Actinomycetes, and Fusarium. Common adverse reactions of voriconazole include neurological dysfunction, visual impairment, liver dysfunction, renal dysfunction, etc. Clinically, more and more attention is given to monitoring the blood concentration of voriconazole. There are different opinions on the specific effective concentration range of voriconazole, but it is agreed that only clinical therapeutic effect is only achieved at > 1-2 ug/m. However, when the minimum blood plasma concentration of voriconazole exceeds 5-6 ug/ml, the incidence of adverse reactions in patients significantly increases. Excessive voriconazole minimum plasma concentration (≥6.0 ug/ml) would likely cause neurotoxicity, visual impairment, and liver toxicity.

Linezolid, as a new type of synthetic oxazolidinone antibacterial drug, mainly binds to the bacterial 23S site of ribosomal RNA of the 50S subunit. This hinders the connection between mRNAs and the ribosome and prevents the formation of a functional 70S initiation complex., and thus inhibits bacterial protein synthesis. It is mainly used clinically for the treatment of bacteremia caused by vancomycin-resistant enterococci, pneumonia, comprehensive skin infections caused by methicillin-resistant Staphylococcus aureus, and bacteremia caused by penicillin-resistant Streptococcus pneumoniae.

Risperidone is a psychiatric drug mainly used to treat schizophrenia, bipolar disorder, and irritability in people with autism. 9-hydroxyrisperidone is the active metabolite of risperidone, so evaluating the total concentration of risperidone and 9-hydroxyrisperidone within the body is of great significance for clinical rational drug use.

Paclitaxel has a good effect in the treatment of ovarian cancer, cervical cancer, and other gynecological tumors, as well as non-small cell lung cancer, and esophageal cancer. Studies have shown that the blood drug concentration of paclitaxel is correlated to its adverse reactions after chemotherapy. When the blood drug concentration of paclitaxel > 0.05 μmol/L, toxic side effects are also observed. Pharmacokinetic methods can detect the blood drug concentration and determine the Tc>0.05 (the time when blood concentration>0.05 μmol/L) to predict the possibility of adverse reaction. Individualized dosing regimens can be formulated according to the results.