Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice

Abstract

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The plasma concentration-time course data were analyzed using a three-compartment open model with zero-order administration and first-order elimination on the NONMEM program. Sixty-one had elevated transaminase levels, and alkaline phosphatase was elevated in 40. Body surface area, albumin, a 1 -acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. Compared to patients with normal or minimal impairment of liver function, patients with grade 2 and 3 elevations of transaminases at baseline in conjunction with elevation of alkaline phosphatase had 22 and 38% lower clearances, respectively. Goodness-of-fit plots indicated that the model was fitted well with the observed data, and the bootstrap method guaranteed robustness of the model. We A nticancer drugs have a narrow therapeutic window, and interpatient variabilities in pharmacokinetics and pharmacodynamics may results in serious toxicities.(1) Elucidating the factors causing these interpatient variabilities is helpful for avoiding serious toxicities and augmenting antitumor activity. Population pharmacokinetics represent a means to investigate the effect of patients' variables on the pharmacokinetics of drugs.(2-4) In this approach, pharmacokinetics are analyzed in many patients with different backgrounds as a population, and the effect of these backgrounds on the pharmacokinetics are investigated. Pharmacokinetic information on patients with small numbers of drug concentration data can also be analyzed by population pharmacokinetic methodology.(2-5) Thus, it is a useful tool for investigating pharmacokinetics of drugs in a population including elderly patients or patients with organ dysfunctions.Docetaxel has been used widely to treat breast, non-small-cell lung, ovarian, head and neck, gastric, esophageal, and prostate cancers. (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) The drug is eliminated from the body mainly by hepatic metabolism. Population pharmacokinetic models of docetaxel have been developed using data obtained from patients treated in clinical trials prior to its drug registration, (16)(17)(18) where body surface area, albumin, age, α 1 -acid glycoprotein, and liver function were found to be significant covariates for the systemic clearance of docetaxel. In clinical studies for the development of anticancer drugs, unfit patients including those with moderate to severe liver dysfunction or poor performance status are commonly excluded, and information on pharmacokinetics and pharmacodynamics for such patients is therefore lacking.Therefore, in the present study, we developed a population pharmacokinetic model of docetaxel in cancer patients treat...

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

“…(4) In observational and retrospective studies, docetaxel clearance is reduced by 12-38% in patients with elevated plasma levels of TB and ⁄ or transaminases. (5,6) Bruno et al (7) showed that clearance was reduced by 27% in patients with ALT or AST >1.59 ULN and ALP >2.59 ULN. In a previous issue in this journal, Minami et al (6) recommended dose reduction by approximately 20% and 40% in patients with grade 2 and 3 elevations of transaminases and elevated ALP based on population PK modeling.…”

“…(5,6) Bruno et al (7) showed that clearance was reduced by 27% in patients with ALT or AST >1.59 ULN and ALP >2.59 ULN. In a previous issue in this journal, Minami et al (6) recommended dose reduction by approximately 20% and 40% in patients with grade 2 and 3 elevations of transaminases and elevated ALP based on population PK modeling. Importantly, as Minami and colleagues noted, this recommendation needs to be validated prospectively.…”

Clinical Trial Simulations for Dosage Optimization of Docetaxel in Patients with Liver Dysfunction, Based on a Log-binominal Regression for Febrile Neutropenia

“…Docetaxel clearance of each patient was obtained from the PPK study of docetaxel developed for Japanese cancer patients. 12) An LBR was performed by a generalized linear modeling method with the log link function and the error term which has a binomial distribution.…”

“…The PPK model of docetaxel developed for Japanese cancer patients is a 3-compartment model with aˆrst-order elimination. 12) The pharmacokinetic model was parameterized in terms of CL (clearance), the volume of distribution of the central compartment (V 1 ) as well as those of two peripheral compartments (V 2 and V 3 ) and intercompartment clearances (Q 2 and Q 3 ). A log-normal distribution was assumed for the inter-individual variabilities of CL, V 1 , V 3 and Q 3 .…”

“…12) In order to evaluate the e‹cacy and safety of these recommended dose reduction strategies, a clinical trial study needs to be conducted where a su‹cient number of patients are allocated and the decision for dose adjustment could be made. However, in real situations, it is di‹cult to recruit a su‹cient number of patients with liver dysfunction for clinical trials because patients with moderate to severe liver dysfunction are usually excluded.…”