Advances in TDM studies of the chemotherapeutic drug, paclitaxel
发布日期：
2024-08-14
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01

Mechanism and clinical application of paclitaxel

Advances in TDM studies of the chemotherapeutic drug, paclitaxel
Paclitaxel is a diterpenoid of the taxane ring that specifically binds to the beta unit of microtubule proteins and triggers chromosomal aberrations by promoting the assembly of microtubules into microtubules and inhibiting the depolymerization of microtubules, which leads to tumor cell death. Paclitaxel also inhibits cell migration and interrupts mitosis, which in turn inhibits tumor cell production. In recent years, the research on the mechanism of action of paclitaxel has been deepening, Wang J et al[1] observed that paclitaxel can induce mitotic arrest of non-endothelial cells, and at the same time inhibit the proliferation and migration of tumor vascular endothelial cells, which has a strong anti-angiogenic effect. In addition, paclitaxel has certain immunological activity and can participate in the regulation of the body's immune function. In conclusion, more and more studies have proved that paclitaxel can exert its anti-tumor effects through multiple pathways. Paclitaxel has been widely used in clinic since its discovery in 1971, and its indications have been expanded from the treatment of ovarian cancer to a variety of malignant tumors such as gastric cancer, lung cancer, esophageal cancer, breast cancer, head and neck tumors. Some studies have shown that paclitaxel is also effective in metastatic renal cancer, colon cancer, pancreatic cancer, prostate cancer, malignant melanoma, retinoma and AIDS-related Kaposi's sarcoma. With the massive application of paclitaxel, many scientific research explorations have been carried out intensively. For example, Chen Y et al[2] found that low-dose paclitaxel administered in 48 h pulses could cause tumor cells to accumulate in the G2/M phase, which is the most sensitive phase to radiotherapy, thus increasing the sensitivity of radiotherapy without increasing the toxicity response. In addition, Campone M et al[3] gave the combination of paclitaxel and everolimus to 16 patients with different types of tumors, and the results showed that everolimus could reduce the dose of paclitaxel used, and increase the body's sensitivity to paclitaxel, and reduce the emergence of drug resistance. These studies have enriched the application of paclitaxel in the field of antitumor and provided sufficient theoretical basis for paclitaxel to play a wide role in the clinic.



02

Pharmacokinetic profile of paclitaxel

Paclitaxel is highly lipophilic, insoluble in water, with a plasma protein binding rate of 89% to 98%, a higher binding rate to albumin, and a large steady-state distribution volume of up to 50-650 L/m2 in the human body. Due to the high lipophilicity of paclitaxel, the drug enters the body and can rapidly enter the hepatocytes by passive diffusion and specifically recognize the Oatp1a/1b transport proteins of the hepatocytes for hepatic metabolism[4]. Subsequently, the metabolites of paclitaxel enter the intestinal tract with bile, and more than 90% are excreted via the feces, with only about 5% passing through renal excretion. Paclitaxel is administered intravenously according to the body surface area, with a dose range of 135-350 mg/m2, and the time of administration mainly focuses on 3 h and 24 h. The average steady state concentration is 0.2-8.45 mg/L. A large number of early pharmacokinetic reports on paclitaxel in humans concluded that the in vivo distribution of paclitaxel is a two-compartment model, with a peak concentration (cmax) and area under the curve (AUC) were related to the administered dose, and its pharmacokinetics showed linear characteristics. However, with the wide application of paclitaxel in the clinic, it was found that the linear model could not describe the complete distribution curve of paclitaxel, and its nonlinear pharmacokinetic characteristics became more and more obvious. It has been reported in the literature that after continuous intravenous administration of paclitaxel for 3 h, the values of cmax and AUC in vivo do not increase disproportionately to the duration of infusion, exhibiting nonlinear pharmacokinetic characteristics[5]. This phenomenon may be related to the wide distribution of the drug in the body, and the saturation of cell membrane transport and tissue binding. The results of the current domestic pharmacokinetic studies on paclitaxel are different. Li Su et al[6] measured the blood concentration of paclitaxel at the end of intravenous drip for 3 h. The result showed that the blood concentration was the highest at the end of intravenous drip, and the maximum concentration was 10.25 mg/L. In the study of Yang Ying et al[7], the maximal concentration of paclitaxel could be reached at the time of intravenous drip for 10 min, and the value was 14.39 mg/L. In addition to the nonlinear pharmacokinetic characteristics, there is also a large individualization of the metabolism of paclitaxel in the body. In addition to the nonlinear pharmacokinetic characteristics, the metabolism of paclitaxel in vivo is also highly individualized, and the clearance rate can be about 10-fold different between individuals. The results of population pharmacokinetic studies have shown that the elimination of paclitaxel in vivo is affected by factors such as gender, body surface area, age, etc., in which the elimination rate of paclitaxel in males is 20% greater than that of females, the elimination rate increases by 9% for every 0.2 m2 increase in body surface area, and the elimination rate increases by 5% for every 10-year increase in age[8-9]. In addition, the rate of paclitaxel elimination was negatively correlated with the level of total bilirubin, with a 14% decrease in the rate of paclitaxel elimination for every 10 µmol/L increase in total bilirubin in the body. The nonlinear pharmacokinetic characteristics of paclitaxel and individualized differences in the body make it difficult to grasp the efficacy of paclitaxel and to control the occurrence of adverse effects. At present, the results of studies on the pharmacokinetics of paclitaxel are not uniform enough, so blood concentration monitoring and individualized pharmacokinetic studies on paclitaxel are still needed.


03

TDM of paclitaxel

TDM refers to the quantitative analysis of the concentration of drugs and their metabolites in biological samples such as blood through the use of various modern analytical methods under the guidance of the principle of pharmacokinetics, in order to explore the relationship between blood drug concentration and efficacy and toxicity response, and then to determine the effective range of blood drug concentration. By this method, the optimal dose of drugs for different patients can be accurately calculated to minimize individualized differences and achieve the purpose of improving efficacy and reducing adverse reactions. At present, drugs for TDM mainly include the following cases: drugs with low therapeutic index, narrow safety range and high toxicity; drugs with non-linear pharmacokinetic characteristics and large individual differences in pharmacokinetics; drugs requiring long-term preventive or therapeutic application; and drugs that can have interactions that lead to changes in blood concentration when used in combination. Several studies have found that the efficacy of paclitaxel and the occurrence of adverse reactions are closely related to blood concentration and drug exposure time, and that dose adjustment to increase the effective blood concentration of drug exposure time is an effective method to improve drug efficacy and reduce adverse reactions. The current study concluded that paclitaxel showed bidirectional elimination in plasma, with a distribution half-life of 0.04-0.52 h and a clearance half-life of 3.8-16.5 h. The average steady-state drug concentration was much higher than the in vivo test effective antitumor concentration [10]. Performing TDM of paclitaxel can scientifically individualize drug administration by systematically evaluating the pharmacokinetic parameters of the drug in vivo in the previous cycle to guide the dosage of the drug during subsequent treatment.


Practical case study of TDM of paclitaxel



Experimental objective: To study the individual differences in pharmacological parameters of paclitaxel in a Chinese breast cancer population receiving paclitaxel chemotherapy by monitoring paclitaxel blood concentration, and to analyze the correlation between the pharmacological parameter of paclitaxel, time to blood concentration of 0.05 μmol/L or more (Tc＞0.05), and its toxicity and efficacy.

Experimental methods: 80 breast cancer patients admitted to the hospital were given a paclitaxel-based neoadjuvant treatment regimen, with every 3-4 weeks as a cycle, and received 2-6 cycles of chemotherapy. Peripheral blood samples were collected at (24 ± 6) h after the start of paclitaxel titration, and paclitaxel blood concentration was measured, and Tc＞0.05 was calculated, according to the calculation results to analyze the variability of different individuals; and according to the Tc＞0.05, the population was divided into 3 groups: >35 h group (greater than the therapeutic window), 26~35 h group (therapeutic window), <26 h group (less than the therapeutic window), and the incidence rate of myelosuppression among the groups was statistically analyzed, and the incidence rate of bone marrow suppression among the different groups was also analyzed. The incidence of myelosuppression and clinical efficacy were statistically analyzed among different groups, so as to explore the correlation between Tc＞0.05 and toxicity and efficacy.

Experimental results: The paclitaxel pharmacologic parameter Tc > 0.05 varied considerably among individuals, with a mean value of 27.35 h and a coefficient of variation (CV) of 27.12%.Thirty-seven patients (46%) with Tc > 0.05 were within the therapeutic window, 11 patients (14%) with Tc > 0.05 , were greater than the therapeutic window, and 32 patients (40%) were below the therapeutic window, as shown in Figure 1. Paclitaxel blood concentrations were normally distributed, ranging from 16 to 156 mg/L, with a mean (61.75 ± 24.89) mg/L, 4 patients had paclitaxel blood concentrations >100 mg/L, and 6 patients had paclitaxel blood concentrations <30 mg/L. The pharmacokinetic parameter of paclitaxel, Tc>0.05, is closely related to the adverse effects of treatment as well as efficacy, and optimizing the dose of neoadjuvant chemotherapeutic agents in breast cancer patients according to the pharmacological parameters can improve the safety and efficacy of paclitaxel administration.

Advances in TDM studies of the chemotherapeutic drug, paclitaxel

Figure 1 Distribution of paclitaxel blood concentration Tc>0.05 in 80 patients


Diagreat has innovatively developed the Paclitaxel Detection Kit (Chemiluminescence Immunoassay), which can simultaneously detect Paclitaxel Injection, Paclitaxel Liposome, and Paclitaxel Albumin Bound, three different preparation types of Paclitaxel, to meet the testing needs of clinical patients. At the same time, by carrying a fully automated chemiluminescence immunoassay analyzer, it is convenient and fast to realize TDM detection, providing TDM solutions for the precise treatment of patients, and scientifically realizing individualized medication[11].


Advances in TDM studies of the chemotherapeutic drug, paclitaxel


Advances in TDM studies of the chemotherapeutic drug, paclitaxel

参考文献

[ 1 ] Wang J，Lou P，Lesniewski R，et al. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly[J]. Anticancer Drugs，2003， 14（1）：13.

[ 2 ] Chen Y，Pandya KJ，Feins R，et al. Toxicity profile and pharmacokinetic study of a phase I low-dose schedule-dependent radiosensitizing paclitaxel chemoradiation regimen for inoperable non-small cell lung cancer（NSCLC） [J]. Int J Radiat Oncol Biol Phys，2008，71（2）：407.

[ 3 ] Campone M，Levy V，Bourbouloux E，et al. Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours[J]. British Journal of Cancer，2009，100（2）：315.

[ 4 ] van de Steeg E，van Esch A，Wagenaar E，et al. High impact of Oatp1a/1b transporters on in vivo disposition of the hydrophobic anticancer drug paclitaxel[J]. Clin Cancer Res，2011，17（2）：294.

[ 5 ] Steed H，Sawyer MB. Pharmacology，pharmacokinetics and pharmacogenomics of paclitaxel[J]. Pharmacogenomics. 2007，8（7）：803.

[ 6 ] 李苏，廖海，詹靖，等.比较白蛋白纳米紫杉醇与含聚氧乙烯蓖麻油紫杉醇在乳腺癌患者的药代动力学[J].中国临床药理学杂志，2010，26（8）：606.

[ 7 ] 杨莹，曹丰.国产紫杉醇在患者血浆中的药代动力学及临床观察[J].中国肿瘤临床与康复，2008（3）：70.

[ 8 ] Joerger M，Huitema AD，Huizing MT，et al. Safety and pharmacology of paclitaxel in patients with impaired liver function：a population pharmacokinetic-pharmacodynamic study[J]. British Journal of Clinical Pharmacology， 2007，64（5）：622.

[ 9 ] Joerger M，Huitema AD，van den Bongard DH，et al. Quantitative effect of gender，age，liver function，and body size on the population pharmacokinetics of Paclitaxel inpatients with solid tumors[J]. Clin Cancer Res，2006，12（7）：2150.

[ 10 ] 滕雪,吴东媛,刘爽,董梅.紫杉醇的治疗药物监测研究进展[J].中国药房,2014,25(48):4598-4601.

[ 11 ] 武渊,张琰,彭伟等.紫杉醇血药浓度监测在乳腺癌新辅助治疗中的临床应用[J].南京医科大学学报(自然科学版),2018,38(05):681-683.





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