Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCI (LY335979)

Research output: Contribution to journalArticle

  • Authors:
  • Sophie Callies
  • Dinesh P. De Alwis
  • Atul Mehta
  • Michael Burgess
  • Leon Aarons

Abstract

Purpose: The impact of zosuquidar.3HCl, an inhibitor of P-glycoprotein, on the pharmacokinetics of daunorubicin and daunorubicinol was examined in a phase I trial using a population approach. Pharmacokinetic and pharmacodynamic properties of zosuquidar.3HCl were also determined. Methods: The pharmacokinetics of daunorubicin and daunorubicinol were studied following daunorubicin administration on day 1 (50 mg/m2 i.v. infusion over 10 min) alone and on day 3 concomitantly with zosuquidar.3HCl (i.v. 200 or 300 mg/m2 over 6 h or 400 mg over 3 h). Of a total of 18 patients entered, 16 with acute leukemia completed the study. Results: A three-compartment pharmacokinetic model adequately described daunorubicin concentration-time profiles. Five- and four-compartment models adequately described the daunorubicin-daunorubicinol pharmacokinetics in the absence and presence of zosuquidar.3HCl, respectively. The impact of zosuquidar.3HCl on coadministered daunorubicin was minimal, with a 10% reduction in daunorubicin clearance. The model predicted a 50% decrease in daunorubicinol apparent clearance in the presence of zosuquidar.3HCl. A direct concentration-effect relationship between zosuquidar.3HCl concentrations and inhibition of rhodamine 123 (Rh123) efflux in CD56 lymphocytes was defined by a sigmoid Emax model. The IC50 was 31.7 μg/l. The zosuquidar.3HCl dosing regimen led to concentrations in excess of the IC90 (169.6 μg/l) and provided maximal P-glycoprotein inhibition during the distribution phases of daunorubicin. Conclusions: The decrease in daunorubicin and daunorubicinol clearance in the presence of zosuquidar.3HCl likely reflects inhibition of P-glycoprotein in the bile canaliculi impeding their biliary excretion. The results need to be interpreted carefully due to the sequential nature of daunorubicin administration and analysis. © Springer-Verlag 2004.

Bibliographical metadata

Original languageEnglish
Pages (from-to)39-48
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number1
DOIs
Publication statusPublished - Jul 2004