Verification of Pharmacodynamic Equivalence of Granule and Capsule Formulations of Bixalomer, A Non-absorbable Phosphate Binder

Abstract

Bixalomer, one of phosphate binders used for the treatment of hyperphosphatemia, is a calcium- and metal-free, non-absorbable amine-functional polymer that decreases serum phosphate levels by binding phosphorus in the gastrointestinal tract. Bixalomer is available in capsule form, and a new granule formulation was recently developed. As this new formulation is expected to provide a new treatment option for chronic kidney disease patients, verification of the equivalence between the two formulations is essential to ensure their clinical compatibility. Equivalence be usually verified by either or both (1) an in vitro dissolution study or (2) an in vivo study using pharmacokinetic endpoints for drugs absorbed into the blood after administration. However, as bixalomer is a non-absorbable compound that acts in the gastrointestinal tract, no dissolution tests or pharmacokinetic evaluations of dosage forms with absorption and systemic delivery were available to verify equivalence. In instances where pharmacokinetic endpoints are unavailable, well justified pharmacodynamic endpoints can be used to demonstrate bioequivalence. Therefore, we set the pharmacodynamic endpoint based on the mechanism of action: the change from baseline in mean daily urinary phosphorus excretion. The two formulations fell within the acceptable range of equivalence, therefore, the granule and capsule formulations were equivalent. This trial provided a novel verification that the equivalence between two bixalomer formulations can be determined by evaluating the change from baseline in mean daily urinary phosphorus excretion as a measure of binding capacity.