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

Callies, S; de Alwis, DP; Mehta, A; Burgess, M; Aarons, L; (2004) Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979). Cancer Chemotherapy and Pharmacology , 54 (1) pp. 39-48.

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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/m(2) i.v. infusion over 10 min) alone and on day 3 concomitantly with zosuquidar.3HCl (i.v. 200 or 300 mg/m(2) 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 E-max model. The IC50 was 31.7 mug/l. The zosuquidar.3HCl dosing regimen led to concentrations in excess of the IC90 (169.6 mug/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

Type: Article
Title: Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979)
Additional information: WoS ID: 000221783000006 JournalEnglishArticleSPRINGER-VERLAG1JUL825UDNEW YORKde Alwis DP Eli Lilly & Co Ltd, Global Pharmacokinet Dept, Erlwood Manor,Sunninghill Rd, Windlesham GU20 6PH, Surrey, EnglandCANCER CHEMOTHER PHARMACOL175 FIFTH AVE, NEW YORK, NY 10010 USA
Keywords: article, BILE, Cancer, CD56, CLEARANCE, CLINICAL- PHARMACOLOGY, COMBINATION, COMPARTMENT, daunorubicin, daunorubicinol, DOXORUBICIN, ENGLAND, excretion, glycoprotein, IMPACT, INHIBITION, INHIBITOR, LEUKEMIA, Lilly, LY335979, lymphocyte, LYMPHOCYTES, model, Models, MULTIDRUG-RESISTANCE MODULATOR, NONMEM, P-GLYCOPROTEIN INHIBITOR, patient, Patients, PHARMACOKINETICS, PHASE-I, PHASE-I TRIAL, population, PSC 833, REDUCTION, REVERSAL, SOLID TUMORS, TRIAL, TRIHYDROCHLORIDE LY335979
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/37143
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