Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model.
Nano- and microparticulate carriers can exert a beneficial impact on the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared with the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by intravenous administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11, and d15. Body weight change and neutropenia were assessed as pharmacodynamic markers of toxicity. The pharmacodynamic markers of antitumor efficacy were increase in lifespan (ILS) and tumor volume progression, measured noninvasively by magnetic resonance imaging. At equivalent doses, neutropenia was similar for both formulations, but weight loss was more severe for Cre-pac. No regimen of Cre-pac extended survival, whereas L-pac at 40 mg/kg x2 doses was well tolerated and mediated 26% ILS (p < 0.0002) compared with controls. L-pac at a lower cumulative dose (20 mg/kg x3) was even more effective (40% ILS; p < 0.0001). In striking contrast, the identical regimen of Cre-pac was lethal. Development of a novel semimechanistic pharmacodynamic model permitted quantitative hypothesis testing with the tumor volume progression data, and suggested the existence of a transient treatment effect that was consistent with sensitization or "priming" of tumors by more frequent L-pac dosing schedules. Therefore, improved antitumor responses of carrier-based paclitaxel formulations can arise both from dose escalation, because of reduced toxicity, and from novel carrier-mediated alterations of antitumor pharmacodynamic effects.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.
Rong
R
Zhou
Richard V
RV
Mazurchuk
Judith H
JH
Tamburlin
John M
JM
Harrold
Donald E
DE
Mager
Robert M
RM
Straubinger
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008962:Models, Theoretical; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D047368:Tumor Burden
D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol