Clinical Pharmacokinetics of Vinblastine by Continuous Intravenous Infusion1

Vinblastine (VLB) is moderately active clinically against ad vanced breast cancer. Since VLB is extensively taken up by platelets and thus only partially available to tumor cells, to enhance the therapeutic index of VLB we have therefore ad ministered this agent by continuous i.v. infusion to patients with advanced breast cancer. In conjunction with the clinical trial, we conducted pharmacokinetic studies of generally tritiated VLB, using radiochemical and Chromatographie techniques. The elimination of VLB from the plasma of patients who re ceived it by 5-day i.v. infusion at 1 to 2 mg/sq m daily was biphasic. In four patients who achieved partial remission, the average plasma half-life of VLB during the terminal phase was 29.4 ±14.6 days, with a total clearance of 36 ±8 ml/kg/hr, and a steady-state apparent volume of distribution of 28.1 ± 8.5 liters/kg. However, in three patients whose disease merely stabilized, the plasma half-life was 6.4 ±1.6 days, the total clearance was 137 ±2.9 ml/kg/hr, and the volume of distri bution was 33.0 ±11.6 liters/kg. In contrast, in five patients with refractory disease, these parameters were 2.3 ±0.3 days, 541 ± 124 ml/kg/hr, and 37.6 ± 8.6 liters/kg. Since the apparent volumes of distributions at steady state did not differ significantly among these three groups, whereas the values of the total clearance were markedly dissimilar, the plasma halflives of VLB were significantly shorter in patients not responsive to continuous infusion therapy with this drug. Although the number of patients studied was small, it nevertheless appears that favorable clinical response of patients with advanced breast cancer is associated with slow total clearance of the drug.