A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979).
OBJECTIVE
To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl.


METHODS
The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg x m(-2) or 225 mg x m(-2)) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1.


RESULTS
The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor ELTM impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 microg x l(-1) x h to 19115 microg x l(-1) x h following paclitaxel 175 mg x m(-2)) when zosuquidar Cmax was greater than 350 microg x l(-1). This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 microg x l(-1)). A standard dose of 175 mg x m(-2) of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition.


CONCLUSIONS
This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 microg x l(-1)) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.
Callies
Sophie
S
Eli Lilly and Company Limited, Windlesham, Surrey, UK.
de Alwis
Dinesh P
DP
Harris
Adrian
A
Vasey
Paul
P
Beijnen
Jos H
JH
Schellens
Jan H
JH
Burgess
Michael
M
Aarons
Leon
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003986:Dibenzocycloheptenes; D004338:Drug Combinations; D011804:Quinolines; C095179:zosuquidar trihydrochloride; D017239:Paclitaxel