Population Analysis of the Pharmacokinetic Variability of High-Dose Metoclopramide in Cancer Patients1

Abstract

Metoclopramide infusions are used to prevent nausea and vomiting in cancer patients during chemotherapy. 47 patients received metoclopramide during 109 chemotherapeutic treatments as a loading (dose range = 0.55 to 4.5 mg/kg over 15 minutes) and maintenance (dose range = 0.57 to 4.8 mg/kg over 8 hours) infusion. During and up to 24 hours after the end of the maintenance infusion between 4 and 10 blood samples were collected per treatment. Metoclopramide was analysed in plasma by liquid chromatography. Pharmacokinetic and demographic data of 83 treatments were analysed by the NONMEM program using a linear 2-compartment model. It was found that bodyweight and serum alkaline phosphatase activity explain some of the interindividual variability in clearance (CL). The typical pharmacokinetic parameters for an average individual (70kg, alkaline phosphatase =100 IU/L) were: CL = 20 L/h; volume of distribution at steady state (Vd_ss) = 190L; terminal half life = 8h. The interindividual variabilities in clearance, volume of central compartment and Vd_ss were 50%, 35% and 35%, respectively. The residual variability in plasma concentrations was estimated as 13%.