Age-related changes in nanoparticle albumin-bound paclitaxel pharmacokinetics and pharmacodynamics: influence of chronological versus functional age

Abstract

Purpose: This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer.

Methods: Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc.

Results: Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041).

Conclusion: A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.

Trial registration: ClinicalTrials.gov NCT00609791.

Keywords: Geriatric oncology; Older adult; Pharmacodynamics; Pharmacokinetics; Taxane.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

©AlphaMed Press.

Figures

Figure 1.

Study schema. ∗, Based on National Cancer Institute Common Terminology Criteria for Adverse Events v3.0: 1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death. Abbreviations: GA, geriatric assessment; nab, nanoparticle albumin-bound; T, time point.

Figure 2.

Graphical representations of the linear regression models predicting plasma pharmacokinetic parameters (ln AUC24, ln CL) as response variables based on the explanatory variables of age and toxicity risk score. The regression line and the data points are presented. (A): ln AUC24 by age: ln AUC = 7.66 + 0.011 × age. Slope = 0.011; SE = 0.0057; p = .055. (B): ln CL by age: ln CL = 3.97 − 0.0074 × age. Slope = −0.0074; SE = 0.0063; p = .25. (C): ln AUC24 by risk: ln AUC = 7.93 + 1.17 × risk. Slope = 1.17; SE = 0.45; p = .013. (D): ln CL by risk: ln CL = 3.87 − 0.96 × risk. Slope = −0.96; SE = 0.44; p = .04. Abbreviations: AUC24, area under the curve (0–24 hours); CL, clearance; SE, standard error.

Figure 3.

Toxicity rate by risk score distribution.