Population pharmacokinetics of docetaxel in patients with solid tumors

Abstract

Objective To explore the characteristics and the cause of variance of pharmacokinetics (PK) of docetaxel (DTX) in patients with solid tumors. Methods Between January 1 of 2018 and December 31 of 2020, 374 patients at two research centers—oncology, breast and thyroid surgery, thoracic surgery, the Third Affiliated Hospital of Chongqing Medical University, and oncology, breast and thyroid surgery, obstetrics and gynecology, Henan Provincial People's Hospital—provided a total of 772 docetaxel plasma samples. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to determine docetaxel plasma concentrations. Nonlinear mixed-effects model (NONMEM) software was used to establish the population phar macokinetics(PPK) model. Using bootstrap and visual predictive check(VPC) for internal validation of the model. Results The current study established a three-compartment PPK model with first-order elimination of docetaxel in patients with solid tumors. DTX blood concentrations ranged from 3.53 ng/mL to 2 491 ng/mL, with a median of 175.5 ng/mL. Albumin (ALB) was identified as a covariate significantly affecting the clearance(CL) of docetaxel, and creatinine(CREA) was a covariate significantly affecting Q3. The model-estimated CL, V2, Q2, and Q3 of docetaxel were 57.2 L/h, 11.8 L, 14.1 L/h, and 8.63 L/h, respectively. Conclusion A three-compartment PPK model with multicenter data is established in patients with solid tumors. ALB is the main factor affecting CL variation. The internal validation results show that the model is stable and reliable.

Keywords

• docetaxel
• population pharmacokinetics
• multicenter
• solid tumors