Pharmacokinetics and biodistribution of paclitaxel following intrauterine administration of PACLIMER® microspheres in female New Zealand rabbits

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Introduction: The efficacy of high-dose chemotherapy in a subset of malignancies suggests that resistance may not be absolute and laboratory studies that show that sufficiently higher doses of most antineoplastic agents overcome all mechanisms of resistance. However, higher doses in patients are associated with unacceptable toxicity which may be circumvented by targeting the drug to the diseased tissues. We have investigated the pharmacokinetics and bio-distribution of paclitaxel, an inhibitor of cell proliferation and angiogenesis, following intrauterine administration of PACLIMER® Microspheres in female New Zealand rabbits. The objective was to deliver high concentrations of the drug to the uterine tissues with low systemic levels for a prolonged period of time to optimize the therapy of cell proliferative and/or angiogenesis-dependent uterine disorders. Method: PACLIMER® microspheres containing 10% paclitaxel in a polymer, Polilactofate™, were suspended in a thermo-reversible gel and administered into the uteri of rabbits at 1, 4 or 7.5mg/kg paclitaxel dose. Plasma samples were obtained at various times up to 4 weeks. At 4 and 8 weeks post-dosing, 3 rabbits in each group were sacrificed and their uteri and other organs were harvested for paclitaxel analysis using a LC-MS-MS method. Results: Paclitaxel was detected in the plasma samples but the concentrations were not dose-dependent. The maximum plasma concentrations measured (at 24 hours) were 0.85, 1.1 and 1.0ng/mL at 1, 4 and 7.5mg/kg dose, respectively. High and dose-dependent uterine tissue concentrations of paclitaxel were observed at 4 and 8 weeks but no drug was detected in the brain, liver, and lung tissues. Up to 10,000-fold higher concentrations of paclitaxel was measured in uterine tissues compared to the plasma. For example, at 4 weeks, the mean plasma concentration for the 7.5mg/kg dose was about 0.44ng/mL while the mean uterine tissue concentration was about 5,150ng/g. The mean uterine tissue concentration at 8 weeks was 366ng/g at 7.5mg/kg dose; plasma levels were below the level of detection (0.1ng/mL). Conclusions: Instillation of PACLIMER® microspheres suspended in a thermo-reversible gel into the rabbit uterus resulted in prolonged and very high concentrations of paclitaxel in the uterine tissue and low concentrations in plasma. This study was partly funded with a 50% matching grant from the Maryland Industrial Partnerships (MIPS).