POPULATION PHARMACOKINETICS OF TOTAL AND UNBOUND ETOPOSIDE

A population pharmacokinetics study using the NONMEM program was under taken to determine the effects of different covariates on the pharmaco kinetic parameters of etoposide. A total of 1,044 plasma etoposide con centrations were determined by high-performance liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25-85 years) tre ated for various tumor types with i.v. (57 pts) or oral (43 pts) etopo side. For 67 pts, etoposide plasma protein binding was deter-mined by equilibrium dialysis; the unbound fraction ranged from 4% to 24%. A li near two-compartment model with first-order absorption (for oral dosin g) accurately described the concentration versus time data. The centra l and peripheral volumes of distribution were significantly correlated with the body surface area [Vc (L) = 5.5 x BSA (m(2)) and Vp = 4.1 x BSA], but even after BSA had been taken into account, the interindivid ual variability of the two volumes remained high (34% and 57%, respect ively). The clearance (CL) was not correlated with the following covar iates: age, BSA, sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 x (1 - 0.009 x PRO)x WT/Scr + 33.8 x (1 - 0.29 x META) x (1 - 0.012 x ALB) , where ALB, PRO, WT, and Scr, respectively, were albuminemia, protein emia (g/l), weight (kg), and serum creatinine (mu M) and META = 1 if t he patient had liver metastases (otherwise, META = 0). The interindivi dual variability in CL (mean value 30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bi oavailability was 66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negative ly correlated with Scr but was not dependent on either PRO or ALB. The se data show that modifications in PRO levels do not directly affect p lasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates such as Scr in e toposide dosing. This population data base will constitute the prerequ isite for adaptative control with feedback dosing for continuous oral administration of etoposide.