Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.
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/m2 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/m2 administered dose averaged 0.89 mg/liter x 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.
Gauvin
A
A
Oncopharmacology Department, Pharmacy Service, Anticancer Center, Montpellier, France.
Pinguet
F
F
Culine
S
S
Astre
C
C
Gomeni
R
R
Bressolle
F
F
D000367:Age Factors; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001499:Bayes Theorem; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018579:Patient Selection; D012984:Software; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine