A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979).
OBJECTIVE
To develop a population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of zosuquidar.3HCl, a potent P-glycoprotein inhibitor.


METHODS
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).


RESULTS
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 (<500 mg). In the presence of high 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 ( P<0.005) was observed when the impact of zosuquidar.3HCl was accounted for.


CONCLUSIONS
This integrated parent-metabolite population pharmacokinetic model accurately characterized the increase in doxorubicin and doxorubicinol exposure (1.33- and 2-fold, respectively) in the presence of zosuquidar.3HCl (>or=500 mg) and provided insights into the pharmacokinetic interaction, which may be useful in designing future clinical trials.
Callies
Sophie
S
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
de Alwis
Dinesh P
DP
Wright
James G
JG
Sandler
Alan
A
Burgess
Michael
M
Aarons
Leon
L
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003986:Dibenzocycloheptenes / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*
D003986:Dibenzocycloheptenes; D011804:Quinolines; D004317:Doxorubicin; C095179:zosuquidar trihydrochloride; C010013:adriamycinol