Biochronomer™ technology and the development of APF530, a sustained release formulation of granisetron.

Granisetron and other 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are first-line agents for preventing chemotherapy-induced nausea and vomiting (CINV). Current treatment guidelines prefer the longer-acting agent, palonosetron, for CINV prevention in some chemotherapy regimens. A new granisetron formulation, APF530, has been developed as an alternative long-acting agent. APF530 utilizes Biochronomer(™) technology to formulate a viscous tri(ethylene glycol) poly(orthoester)-based formulation that delivers - by single subcutaneous (SC) injection - therapeutic granisetron concentrations over 5 days. The poly(orthoester) polymer family contain an orthoester linkage; these bioerodible polymer systems are specifically designed for controlled, sustained drug delivery. Pharmacokinetics and pharmacodynamics of APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively) administered 30-60 minutes before chemotherapy were evaluated in two Phase II trials in cancer patients receiving moderately (MEC) or highly (HEC) emetogenic chemotherapy. Pharmacokinetics were dose proportional, with slow granisetron absorption and elimination. Both trials demonstrated similar results for median half-life, time to maximum concentration, and exposure for APF530 250 and 500 mg, with no differences between patients receiving MEC or HEC. A randomized Phase III trial demonstrated noninferiority of APF530 500 mg SC (granisetron 10 mg) to intravenous palonosetron 0.25 mg in preventing CINV in patients receiving MEC or HEC in acute (0-24 hours) and delayed (24-120 hours) settings, with activity over 120 hours. Mean maximum granisetron plasma concentrations were 10.8 and 17.8 ng/mL, and mean half-lives were 30.8 and 35.9 hours after SC administration of APF530 250 and 500 mg, respectively. Therapeutic granisetron concentrations were maintained for greater than 120 hours (5 days) in both APF530 dose groups. These data suggest that APF530 - an SC-administered formulation of granisetron delivered via Biochronomer technology - represents an effective treatment option for the prevention of both acute and delayed CINV in patients receiving either MEC or HEC.