Antineoplastics in Cancer Therapy

The market leading cytotoxic taxanes paclitaxel and docetaxel have negligible oral bioavailability due to their degradation by CYP 3A. This is a common problem with large molecule, natural product-derived antineoplastics and results in many examples of this class of drug being administered intravenously (IV) rather than orally.

An important target for BAS in this therapeutic area is paclitaxel. The patient population for paclitaxel in the U.S. in 2002 was about 175,000. Paclitaxel treatments are expected to grow at a rate of over 10% annually because of the aging U.S. population. Paclitaxel is labeled for many different cancer treatments and is used primarily for breast, ovarian and non-squamous cell lymphoma.

In cancer therapy all cancer cells must be killed to prevent recurrence of the cancer. Therefore it is standard practice to use the highest dose of an antineoplastic drug that the patient is able to tolerate and to treat the patient as often as is possible. Most antineoplastic drugs are developed for intravenous use in order to bypass problems of absorption and pre-systemic metabolism that would impact the attainment of a high blood concentration of the administered pharmaceutical. However, oral treatment with anticancer agents would generally be preferred if oral bioavailability were adequate. IV delivery of antineoplastics is not amenable to self-administration resulting in expensive hospitalization, at a minimum as an outpatient. Although IV dosing is high intensity, it is usually less frequent than if there are options to orally dose at home. Chemotherapy, in most instances, would be more effective with a higher dosing frequency, particularly if lower doses could be used in order to reduce adverse effects. There are, therefore, many factors which would make oral dosing an improvement in cancer care over existing IV formulations.

A paclitaxel IV dosage is difficult to formulate due to the poor solubility of the active in water. In order to improve the solubility and enable intravenous solutions to be prepared, paclitaxel is formulated with Cremophor EL™, a polyethoxylated castor oil, and ethanol. Cremophor EL™ has been shown to be toxic, producing vasodilation, labored breathing, lethargy, hypertension and death in dogs following IV administration. The paclitaxel/Cremophor EL™/ethanol formulation has also been shown to induce allergic reactions with most of the atypical human side-effects attributed to the Cremophor EL™ component. This has necessitated that typical IV therapies be carried out with extremely long infusion times between three hours and twenty-four hours. Paclitaxel is therefore an attractive target for an application of the BAS Booster. It is a market leader, generic, and there are specific problems with the IV formulation that would make an oral dose very attractive to physicians and patients even at a premium price to available generics.


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