The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination

Abstract

A radioimmunoassay has been used to investigate the pharmacokinetics of vincristine in 39 cancer patients who received between 0.4 and 1.54 mg vincristine/m2 as part of standard treatment protocols. There was wide interindividual variation in both the terminal elimination half-life of vincristine (t1/2beta) and the associated volume of distribution (Vd), resulting in an 11-fold range of dose-corrected area under the plasma concentration versus time curve values (AUC0-infinity). Elevated vincristine AUC0-infinity values were observed in those patients with raised serum alkaline phosphatase at the time of vincristine estimation. The t1/2beta was significantly longer in these patients than in those with serum alkaline phosphatase within normal limits, suggesting that biochemical evidence of cholestasis is associated with reduced clearance of vincristine. Evidence is also presented to suggest that the clearance of vincristine is dose-dependent within the therapeutic dose range. We observed a disproportionate rise in vincristine plasma concentration at doses exceeding t1/2beta compared with that observed for patients receiving 1 mg vincristine/m2 or less.