Differential Pharmacodynamic Effects of Paclitaxel Formulations in an Intracranial Rat Brain Tumor Model

Abstract

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 ϫ2 doses was well tolerated and mediated 26% ILS (p Ͻ 0.0002) compared with controls. L-pac at a lower cumulative dose (20 mg/kg ϫ3) was even more effective (40% ILS; p Ͻ 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 carriermediated alterations of antitumor pharmacodynamic effects.The treatment of malignant brain tumors presents continuing challenges. Conventional therapy by surgical debulking and followed by radiation and chemotherapy generally is not curative. Chemotherapy fails for pathophysiological, pharmacological, and pharmaceutical reasons. Poor perfusion, tortuous and poorly permeable vasculature, and drug resistance are tumor properties that hinder drug penetration, deposition, and retention (Trédan et al., 2007). Suboptimal drug properties, including poor intrinsic membrane and tissue permeability, short circulating half-life, and rapid metabolism also impede therapy.Incorporation of drugs in particulate carriers such as emulsions, nanoparticles, or liposomes may provide the means to overcome several of these factors. By limiting the drug volume of distribution, the carrier can reduce toxicity to normal tissues, permitting higher doses and thereby overcoming functional resistance (Drummond et al., 1999). In addition, carriers may extravasate through the flawed tumor microvasculature, increasing drug deposition and antitumor effects (Sharma et al., 1997;Zhou et al., 2002;Arnold et al., 2005).Paclitaxel is a clinically important cytostatic/cytotoxic agent that also exerts potent antiangiogenic effects (Be...

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