Bayesian Estimate of Vinorelbine Pharmacokinetic Parameters in Elderly Patients with Advanced Metastatic Cancer
2000
The
objective of the present study was to determine the pharmacokinetic
profile of vinorelbine in patients 65 years or older with metastatic
cancer in progression. Twelve patients were enrolled in this study.
Vinorelbine was administered by a 10-min continuous infusion at a dose
of 20–30 mg/m 2 through a central venous catheter.
Chemotherapy was repeated weekly. A total of 46 courses of vinorelbine
was studied. Each patient underwent pharmacokinetic evaluation during
the first cycle of treatment. Toxicity evaluation was carried out
before each course of chemotherapy. Plasma vinorelbine determinations
were performed by high-performance liquid chromatography with
spectrofluorometric detection. A Bayesian estimation of
individual pharmacokinetic parameters was carried out using the
nonlinear mixed-effect modeling approach as implemented in the NONMEM
computer program. An open three-compartment pharmacokinetic model with
a zero order input rate was used to describe the kinetics of
vinorelbine. Area under the plasma-concentration time curve (AUC)
normalized to a 30 mg/m 2 administered dose averaged 0.89
mg/liter × h (coefficient of variation = 23.7%). The total
plasma clearance averaged 0.93 liter/h/kg (0.61–1.83 liter/h/kg;
coefficient of variation = 38.6%). The elimination half-life was
38.1 ± 5.8 h. A high correlation was found between patient
age and total clearance ( r = −0.8; P < 0.001). The main hematological toxicity observed was anemia in 11
patients. Neutropenia occurred in 50% of patients. Significant
correlations were found between AUC and the decrease in the hemoglobin
level ( r = 0.60) and between AUC and the decrease in
the neutrophil count ( r = 0.66). Thrombocytopenia was
observed in only one patient. In conclusion, the age-related decrease
in clearance found in this study supports the design of a Phase I study
of vinorelbine in patients older than 65 years or perhaps 70 years.
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