A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979)

To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. The population approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had receive...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2003-02, Vol.51 (2), p.107-118
Main Authors: CALLIES, Sophie, DE ALWIS, Dinesh P, WRIGHT, James G, SANDLER, Alan, BURGESS, Michael, AARONS, Leon
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Biological and medical sciences
Chemotherapy
Cohort Studies
Dibenzocycloheptenes - administration & dosage
Dibenzocycloheptenes - pharmacology
Doxorubicin - analogs & derivatives
Doxorubicin - pharmacokinetics
Drug Interactions
Drug Resistance, Multiple
Female
Humans
Male
Medical sciences
Middle Aged
Models, Biological
Pharmacology. Drug treatments
Quinolines - administration & dosage
Quinolines - pharmacology
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Summary:To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor. The population approach was used (implemented with NONMEM) to analyse doxorubicin-doxorubicinol pharmacokinetic data from 40 patients who had received zosuquidar.3HCl and doxorubicin intravenously (separately in cycle 1 and concomitantly in cycle 2 over 48 h and 0.5 h, respectively). A five-compartment pharmacokinetic model (including three compartments for doxorubicin pharmacokinetics with two pathways for doxorubicinol formation) best described the doxorubicin-doxorubicinol pharmacokinetics in the presence of zosuquidar.3HCl. Doxorubicin clearance (CL), peripheral volume of distribution (V2) and doxorubicinol apparent clearance (CLm/fm) and apparent volume of distribution (Vm/fm) were 62.3 l/h, 2360 l, 143 l/h and 3150 l, respectively, in the absence or presence of low doses of zosuquidar.3HCl (or=500 mg), these values decreased by 25%, 26%, 48% and 73%, respectively, and doxorubicinol pharmacokinetics were characterized by a delayed t(max) (24 h versus 4 h), which led to the inclusion of the parallel pathways. A decrease in the objective function ( Por=500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-002-0542-3