A Research About Inter-patient Variability Of Docetaxel Pharmacokinetic Parameters And Its Relationship With Hematological Toxicity

Background and Purpose: Docetaxel is widely used to treat a wide range of different types of tumors(non-small cell lung cancer, breast cancer, gastric cancer and ovarian cancer et al.), however, the major adverse effect of which is dose-limiting toxicity. In clinical practice, 3/4 grade neutropenia and febrile neutropenia(FN) remain a common life-threatening complication of cancer chemotherapy. The purpose of this research is to entabilish a mathematical model predicting hematological toxicity using docetaxel AUC by analysing intra-patient variability of doceataxel pharmacokinetics parameters and its relationship with hematological toxicity.Methods: Thirty two patients were enrolled into the present research which was conducted at Shandong Cancer Hospital from 2014-10 to 2015-12, including 21 patients with NSCLC, 8 patients with breast cancer and 3 patients with other types of tumors. All this 32 patients received docetaxel monotherapy and the following limited sampling strategy was chosen for the current study: sampling time points at 10 minutes before the end of infusion and 30 minutes after the end of infusion. Docetaxel plasma concentration was detected using Mycare? kit and AUC was calculated using nonparametric mised-effects models. Intra-patient AUC variability, the relationship between AUC and decreased percentage of neutrophils, and the relationship between AUC and incidence rate of 3/4 grade neutropenia were analysed after AUC data was normalized.Results: 1. AUC of 32 patients in the first course was ranged from 1.8ug.h/ml-4.7ug.h/ml and the mean AUC was 3.32±0.12 ug.h/ml after AUC data was normalized by 75mg/m2. The difference between the maximum value and minimum one is 2.6 times. 2. The mean AUC value of doxetaxel in 1-4 course was 3.32 ug.h/ml、3.41 ug.h/ml、3.46 ug.h/ml、3.47 ug.h/ml after AUC value was normalized and AUC value had an increasing tendency with course number. However, number of chemotherapy courses had no correlation with doxetaxel AUC(F=0.186, P=0.824), that means that there is no significant difference of doxetaxel AUC among different courses when a patient receive same dosage during the whole treatment. 3. The model predicting decreased persentage of neutrophils using docetaxel AUC was set as y1 = 1.4812x2 + 3.0217 x + 29.061(course 1), y2 = 4.3981x2 + 14.006 x + 50.532(course 2), y3 = 2.0683x2 + 2.1257 x + 19.604(course 3), y4 = 4.683x2- 19.273 + 61.398(course 4); predicting the incidence rate of 3/4 grade neutropenia using doxetaxel AUC was set as y=19.383ln(x)+2.4005.(x=AUC)Conclusions: The major toxic side effects of docetaxel was neutropenia. This present research verified the greater inter-patient variability of AUC when patients received BSA-based dosage of docetaxel and set up a mathematical model to predict decreased percentage of neutrophil and incidence rate of 3/4 grade neutropenia. This research also provide basis for screening high-risk patients who may suffer seriously hematological toxicity and lay a theoretical foundation for individualized dosage based on doxetaxel AUC. In addition, no statistically significant differences in doxetaxel AUC among different chemotherapy courses was observed if a patient receive the same doge of docetaxel. That means that AUC in the first course has important reference value.