A novel Ondansetron extended release injectable suspension (OERIS): evaluation of Safety, tolerability and pharmacokinetics in a phase I trial.

PURPOSE: Chemotherapy-Induced Nausea and Vomiting (CINV) has a significant negative impact on cancer chemotherapy and patients' quality of life (QOL). Purpose of this study is to establish the safety, tolerability and pharmacokinetics of novel Ondansetron Extended Release Injectable Suspension (OERIS) through preclinical and clinical studies. Antiemetic medications, especially 5-HT3 antagonists like ondansetron, granisetron, neurokinin1 antagonists (aprepitant, fosaprepitant etc.) have proven to be effective in the prevention and control of CINV. However, ondansetron is currently available as oral tablet/solutions or IM/IV formulations requiring multiple dosing 3-5 days during chemotherapy. Novel OERIS formulation is developed with an aim to provide a single dose treatment strategy for an effective prophylaxis of acute and delayed phases of CINV.

METHODS

Preclinical studies in rats and dogs viz. maximum tolerated dose, sub-acute toxicity and pharmacokinetic studies were conducted to support safety and pharmacokinetic assessments and before initiating human studies. Subsequently, a Phase I study was conducted in 24 healthy male human volunteers to evaluate safety, tolerability and pharmacokinetics. Study involves 4 arms with 6 subjects in each arm administered with either one of the 3 doses of OERIS (35, 70 and 100 mg, IM) or reference (24 mg, IV in 3 divided doses).

RESULTS

No Observed Adverse Effect Level (NOAEL) was found to be 150 mg/kg, i.m. in rats, which is approximately 160 times that of recommended ondansetron human dose (0.15 mg/kg, i.v.). Phase I study of OERIS demonstrated optimal PK exposures for efficacy up to 5-days within therapeutic window along with good safety (no QT prolongation and no hypokalemia) and tolerability (no injection site reactions) in healthy subjects at a dose of 100 mg.

CONCLUSION

OERIS is a promising, convenient, safe anti-emetic therapy effective for acute and delayed phases (lasts for 5-days) of CINV in patients receiving chemotherapy with a single dose.

TRIAL REGISTRATION: The trial is registered at Clinical Trial Registry of India (CTRI) with registration number: CTRI/2022/07/043886 (Registered on: 11/07/2022).