Interdisciplinary Science and the Design of a Single-Dose Antibiotic Therapy

Azithromycin is a unique antibiotic due to its serum half-life of 69 h. This half-life is long enough to permit administration of an entire course of therapy in a single dose, if the gastrointestinal (GI) side effects of such a high dose can be minimized. A series of exploratory clinical pharmacology studies were carried out to understand the site-specific absorption and toleration constraints involved in delivering a 2 g oral single-dose regimen. These studies demonstrated that (a) GI side effects were locally mediated in the GI tract, (b) the duodenum was more sensitive than the ileocecal region, and (c) colonic absorption was limited. A novel controlled release suspension dosage form was designed to meet these constraints, and was shown to deliver the desired systemic dose with acceptable toleration. This dosage form, Zmax®, is an oral powder-for-constitution which possesses two major features: (a) 200 μm controlled release microspheres which release the drug as they transit down the small intestine, and (b) alkalizing agents which raise the pH of the gastric milieu for ～20 min to minimize gastric release of the drug (which has high solubility at low pH), in order to minimize exposure of the drug to the sensitive duodenal region. The ability to provide a high single dose of azithromycin results in “front-loading” the mononuclear and polymorphonuclear leukocytes which concentrate the drug and carry it to sites of infection. This provides high drug concentrations early on at infection sites, when the bacterial burden is greatest, potentially improving efficacy and potentially overcoming resistant bacterial strains. Finally, this revolutionary single dose formulation gives 100% compliance, which maximizes the likelihood of therapeutic success.