title: 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).
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Nicholas Li-Xun
authors.identifier: http://orcid.org/0000-0002-6343-176X
authors.initials: NL
authors.lastname: Syn
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
authors.forename: Andrea Li-Ann
authors.initials: AL
authors.lastname: Wong
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
authors.forename: Mu-Yar
authors.initials: MY
authors.lastname: Soe
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chuah
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chan
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
authors.forename: Sing-Huang
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Ross Andrew
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.|Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D012372:ROC Curve; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel
keywords: Antineoplastic combined chemotherapy protocols; biomarkers; neutropenia; pharmacokinetics; taxoids