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 ≤53 upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate -any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-103 ULN, and ⁄ or total bilirubin ≤1-1.53 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 mgÁh ⁄ 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).H epatic dysfunction is a rare comorbidity affecting approximately 0.2% of cancer patients, (1) making it particularly challenging to accrue patients with hepatic dysfunction in oncology trials that assess its effects on the pharmacokinetics and safety profile of chemotherapeutic agents. The paucity of guidance on the treatment of this patient subpopulation can be a real practice issue in clinical oncology; many drugs that form the backbone of chemotherapy have narrow therapeutic windows and are often dosed close to maximally tolerable levels. Unacceptable toxicities can quickly set in if the implications of a reduced hepatic metabolic capacity are not properly regarded, as hepatic drug biotransformation is the predominant route of elimination for many cytotoxic agents.(2) We therefore propose that it may be helpful to risk-stratify cancer patients before starting them on a personalized d...

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients

“…The current study could not establish the role of hepatic impairment on Cl due to the lack of an adequate number of patients with altered liver function. However, the data in limited number of patients corroborate the findings from previous studies notably by Syn 17,20 The other covariates such as age, sex, BSA, Alb, creatinine Cl could not significantly explain the IIV to recommend a dose modification for docetaxel.…”

“…However, the data in limited number of patients corroborate the findings from previous studies notably by Syn et al and Minami et al who recommended 20%–54% reduction in the dose of docetaxel in patients with mild to moderate hepatic impairment based on up to 50% lower Cl observed in such patients. 17 , 20 The other covariates such as age, sex, BSA, Alb, creatinine Cl could not significantly explain the IIV to recommend a dose modification for docetaxel.…”

“…17 In a prospective study by Syn et al there was noted a 28% and 50% reduction in median Cl in patients with mild and moderate hepatic impairment respectively. 20 Interestingly, the docetaxel regimen used in various populations is highly variable. 21 In Caucasians, the routinely used starting doses are 100 mg/m 2 , while in the Asian continent, it is 75 mg/m 2 .…”

“… 17 In a prospective study by Syn et al there was noted a 28% and 50% reduction in median Cl in patients with mild and moderate hepatic impairment respectively. 20 …”

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

“…The Child-Pugh system has commonly been employed to classify patients with hepatic impairment but more recently the NCI scale has been adopted since it provides an objective way of assessing hepatic dysfunction and has more discriminatory power to segregate patients accurately [33,34] .…”