Background: Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy.
Methods: In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated.
Results: APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in ≤20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in ≥80% and ≥75% of patients in both trials with the 250 and 500 mg doses, respectively.
Conclusion: After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron levels for ≥5 days.

Keywords: cancer, chemotherapy-induced nausea and vomiting, subcutaneous


Control of cancer chemotherapy-induced nausea and vomiting (CINV) is paramount in maintaining patients’ quality of life and their compliance with later chemotherapy.1 Regimens may be classified as moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC), on the basis of the emetogenic potential of the individual agents.2 Prevention of CINV is the goal; available antiemetics include serotonin (5-HT3) receptor antagonists, neurokinin 1 (NK-1) receptor antagonists, and dexamethasone. Guidelines on the use of these agents in CINV management, based on the emetogenic potential of the chemotherapy regimen, have been published.1,3,4 Delayed-onset CINV (occurring more than 24 hours after chemotherapy) is typically more difficult to control than acute-onset CINV (occurring 0–24 hours after chemotherapy),1,3,4 and despite available antiemetics, CINV is undertreated, with more than 30% of patients continuing to experience CINV with current antiemetic treatments.4,5

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APF530 is a subcutaneous (SC), sustained-release formulation of 2% granisetron in a polymer vehicle designed to provide a therapeutic level of the drug for ≥120 hours.6 A double-blind, placebo-controlled, intrapatient dose-escalation Phase I study in healthy male subjects determined that single SC doses of APF530 are safe and well tolerated at 125, 250, 500, and 1,000 mg, with mild injection site reactions, no serious adverse events (AEs), and no clinically significant laboratory abnormalities or electrocardiographic (ECG) changes.7,8

The two previously unpublished Phase II studies presented here assessed the pharmacokinetic properties, safety, and efficacy of three doses of APF530, in patients receiving MEC or HEC.