Abstract 1425: Prospective evaluation of serum unbound fraction of docetaxel as a key determinant of its pharmacokinetics and neutropenia in the elderly
Authors: Kenmotsu Hirotsugu , Imamura Chiyo K. , Ono Akira , Omori Shota , Nakashima Kazuhisa , Wakuda Kazushige , Taira Tetsuhiko , Naito Tateaki , Murakami Haruyasu , Takahashi Toshiaki , Tanigawara Yusuke 
Published: July 2016

Background: Although elderly patients are at increased risk for treatment-related toxicities of docetaxel (DOC), total body clearance (CL) is unaltered by advanced age. Because the elderly patients show large interindividual variability in pharmacokinetics and toxicities, the profiles of DOC in older patients remain unclear. The present prospective study was conducted to elucidate a key determinant of pharmacokinetics and hematological toxicities of DOC in the elderly focusing on the unbound fraction in serum.

Patients and Methods: DOC was administered at a dose of 60 mg/m2 once every 3 weeks to patients with non-small cell lung cancer. Pharmacokinetics and toxicity were assessed during the first cycle of therapy. Blood samples were taken immediately before and at the end of the DOC infusion, and at 3 points until 24 h. Unbound DOC was obtained by equilibrium dialysis, and DOC concentrations were determined by the UPLC-MS/MS method. Population pharmacokinetic (PPK) analysis was performed using NONMEM version 7.3.

Results: Of 51 patients treated, median age was 66 years (range 34-84 years), alpha1-acid glycoprotein (AAG) level was 1.21 g/L in median (range 0.5-2.64 g/L), and albumin (ALB) level was 37 g/L in median (range 22-48 g/L). The estimated CL, area under the concentration-time curve (AUC), volume of distribution of the central component (V1), volume of distribution at steady state (Vss) and serum unbound fraction were 23.91 ± 5.78 L/hr, 4.22 ± 1.24 mg/hr/L, 9.10 ± 0.94 L, 128.44 ± 9.09 L, and 0.08 ± 0.03, respectively (mean ± SD). In the PPK analysis, levels of serum proteins were significant covariates affecting pharmacokinetics of DOC but age was not statistically significant. AAG and ALB were associated with CL and V1 (both p&lt;0.01), respectively. In addition, significant correlation was observed between unbound fraction and AAG (p&lt;0.01) which is the major binding protein of DOC, whereas ALB showed marginal correlation (p = 0.055). In 49 patients evaluable of adverse events, decrease in neutrophil counts was well correlated with AUC of unbound DOC (p&lt;0.05), but not with total drug AUC.

Conclusion: Pharmacokinetics of DOC, which is bound to serum proteins extensively (&gt;90%), was influenced by not only AAG but also ALB levels in serum. The key determinant of DOC pharmacokinetics was the unbound fraction caused by individual variations in AAG and ALB levels regardless of patients’ age. The present results suggest that the severe hematologic toxicity induced by higher unbound exposure can be predicted by serum protein levels in patients treated with DOC and it is useful especially for the elderly.

Citation Format: Hirotsugu Kenmotsu, Chiyo K. Imamura, Akira Ono, Shota Omori, Kazuhisa Nakashima, Kazushige Wakuda, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Toshiaki Takahashi, Yusuke Tanigawara. Prospective evaluation of serum unbound fraction of docetaxel as a key determinant of its pharmacokinetics and neutropenia in the elderly. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1425.