The effects of advanced age and serum α₁‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients

Abstract

Aimα1‐Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose‐limiting toxicity, in cancer patients.MethodsDocetaxel was administered at 60 mg m−2 to 51 patients with non‐small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia.ResultsClearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration–time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 μg·h ml−1, 95% CI; 0.329–0.448 μg·h ml−1) compared with patients aged <75 years (0.310 μg·h ml−1, 95% CI; 0.268–0.352 μg·h ml−1). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC.ConclusionRegardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose‐limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel.

Intratumoral Comparison of Nanoparticle Entrapped Docetaxel (CPC634) with Conventional Docetaxel in Patients with Solid Tumors

“…(31,32) Several retrospective studies suggest that the C max of docetaxel is the driver of neutropenia. (6,(33)(34)(35) This is supported by the fact that, despite the lower plasma AUC of conventional docetaxel compared to CPC634, the incidence of grade 3 or 4 neutropenia in this study was significantly higher during conventional docetaxel treatment (70% for conventional docetaxel versus 3% for CPC634).…”

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials

“…Different studies have investigated the relationship between toxicity after IV docetaxel treatment and high levels of unbound docetaxel and low AAG plasma levels. 10 , 56 Low AAG levels were associated with the development of oral mucositis and rash in breast cancer patients and were predictive for response and better overall survival after treatment with IV docetaxel in another study in NSCLC patients. 57 , 58 However, the fraction of unbound docetaxel is impacted by polysorbate-80 in the IV formulation, which is lacking in the oral docetaxel formulation.…”

Profiling Docetaxel in Plasma and Urine Samples from a Pediatric Cancer Patient Using Ultrasound-Assisted Dispersive Liquid–Liquid Microextraction Combined with LC–MS/MS

“…Thus, in the case of pediatric patients, several other factors, such as age and liver function, should be taken into consideration, as the activity of CYP3A4-and hence liver metabolism-could influence the elimination of DOC from the body [38]. In addition, studies examining the pharmacokinetics of DOC have shown that differences in the composition of plasma proteins, especially acid glycoprotein α1, may impact the level of this drug [8,39,40]. Therefore, to improve the efficiency of treatment, it is crucial to develop a methodology that can be applied in TDM studies to allow the adjustment of the optimal dose of DOC in paediatric oncological patients.…”