Population pharmacokinetic model for daunorubicin and daunorubicinol coadministered with zosuquidar.3HCl (LY335979).
OBJECTIVE
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 E(max) model. The IC(50) was 31.7 microg/l. The zosuquidar.3HCl dosing regimen led to concentrations in excess of the IC(90) (169.6 microg/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.
Callies
Sophie
S
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PL, UK.
de Alwis
Dinesh P
DP
Mehta
Atul
A
Burgess
Michael
M
Aarons
Leon
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001648:Bile Canaliculi; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D003986:Dibenzocycloheptenes / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D006801:Humans; D008962:Models, Theoretical; D011804:Quinolines / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003986:Dibenzocycloheptenes; D011804:Quinolines; C095179:zosuquidar trihydrochloride; C000847:daunorubicinol; D003630:Daunorubicin