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Phase 1 and pharmacokinetic study of AI-850, a novel microparticle hydrophobic drug delivery system (HDDS) for paclitaxel
... The data presented herein demonstrate that rapidly dissolving porous particles can be used for intravenous delivery of hydrophobic drugs such as paclitaxel. A Phase I clinical study of AI-850 was recently completed (40). ...
To develop a rapidly dissolving porous particle formulation of paclitaxel without Cremophor EL that is appropriate for quick intravenous administration.
A rapidly dissolving porous particle formulation of paclitaxel (AI-850) was created using spray drying. AI-850 was compared to Taxol following intravenous administration in a rat pharmacokinetic study, a rat tissue distribution study, and a human xenograft mammary tumor (MDA-MB-435) model in nude mice.
The volume of distribution and clearance for paclitaxel following intravenous bolus administration of AI-850 were 7-fold and 4-fold greater, respectively, than following intravenous bolus administration of Taxol. There were no significant differences between AI-850 and Taxol in tissue concentrations and tissue area under the curve (AUC) for the tissues examined. Nude mice implanted with mammary tumors showed improved tolerance of AI-850, enabling higher administrable does of paclitaxel, which resulted in improved efficacy as compared to Taxol administered at its maximum tolerated dose (MTD).
The pharmacokinetic data indicate that paclitaxel in AI-850 has more rapid partitioning from the bloodstream into the tissue compartments than paclitaxel in Taxol. AI-850, administered as an intravenous injection, has been shown to have improved tolerance in rats and mice and improved efficacy in a tumor model in mice when compared to Taxol.
... [22] AI-850 (Acusphere) I Cancer Oral hydrophobic drug delivery system. [94,95] Simotaxel (10; Figure 4) ...
This review covers advances in the discovery, preclinical and clinical development of potential anticancer agents based upon the diterpenoid taxane skeleton. The anticancer properties of approved clinical agents of this class are not discussed, but the review documents how, 13 years post-approval of paclitaxel (Taxol), the base taxane structure is still utilized as the starting skeleton for molecules with improved pharmacological and toxicological properties. Paclitaxel may in fact be the first example of a 'tunable' anticancer agent. In addition, paclitaxel, and perhaps other taxanes in due course, has activities beyond the known antitumor indications, with an example being the use of paclitaxel-coated stents in cardiovascular therapies.
There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.
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