A Bioequivalence Study of Two Different Formulations of Chlorambucil in Beagle Dogs

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Chronic Lymphocytic Leukemia (CLL) in dogs represents an unmet veterinary need. The literature reports a response rate of 70% to protocols using vincristine, prednisone, and chlorambucil combinations; with chlorambucil as the maintenance drug. However, despite therapy for CLL being generally rewarding, the mainstay treatment, chlorambucil, is not an FDA approved drug for veterinary use. Presently, chlorambucil licensed for human use is being used off-label, however currently available tablet sizes, 2 mg, of chlorambucil present a challenge for treating dogs at standard prescribed dosages. Due to this challenge, unregulated compounded chlorambucil products, with reports of varying potency and stability, are in wide use in veterinary care with increased risk to the animal population, as well as the owners, pharmacists, and the veterinarians handling these compounded products. As a result, there is a clinical need for a veterinary specific chlorambucil product, developed and manufactured to the highest quality and safety standards, and at the appropriate strength to facilitate accurate dosing in small animals. Chlorambucil 1 mg tablets are being developed to address the limitations of the 2 mg tablets licensed for human use. This product is a Minor Use and Minor Species (MUMS) designated investigational product that is eligible for conditional approval. The proposed study will contribute to completing the requirements of the safety technical section for the designated intended use in dogs with CLL. The safety of chlorambucil 1 mg tablets for the treatment of CLL has been previously established in a target animal safety study using the reference product. This bioavailability study is designed to evaluate the in vivo comparability of two formulations, termed test and reference, of chlorambucil 1 mg tablets in healthy dogs thereby enabling bridging of the previously established safety information of the reference product to the test product. This study will be a randomised, non-terminal GLP (Good Laboratory Practices) study in purpose-bred beagle dogs. The primary outcome variables will be AUC(0-t) and Cmax.