Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study

Abstract

Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild--alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate--any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-10× ULN, and/or total bilirubin ≤1-1.5× ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg/m(2) docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L/h/m(2) in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mg·h/L in Categories 1, 2, and 3, respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements. (ClinicalTrials.gov registration no. NCT00703378).

Keywords: Antineoplastic combined chemotherapy protocols; biomarkers; neutropenia; pharmacokinetics; taxoids.

© 2015 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1

Non‐compartmental pharmacokinetics of docetaxel in cancer patients categorized according to hepatic dysfunction: Category 1, normal; Category 2, mild – alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate – any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5–10× ULN, and/or total bilirubin ≤1–1.5× ULN. (a) Mean docetaxel concentrations. (b) Docetaxel clearance. (c) Docetaxel exposure. (d) Changes in docetaxel clearance between baseline and repeat pharmacokinetic measurement. AUC, area under the concentration–time curve.

Figure 2

Pharmacodynamics of docetaxel‐induced neutropenia. (a) Mean ± SD of nadir absolute neutrophil count (ANC). (b) Mean ± SD of the maximum decrease between ANC at baseline compared to nadir. Three patients from Category 1 were switched to the 3‐weekly cycle when the repeat pharmacokinetic assessment was carried out, and were thus excluded from pharmacodynamic analysis. Hepatic dysfunction categories were defined as: Category 1, normal; Category 2, mild – alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate – any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5–10× ULN, and/or total bilirubin ≤1–1.5× ULN. Std, standard.