This study will assess the pharmacokinetics (PKs), safety and tolerability of ASP-001 in healthy volunteers. ASP-001 is an orally disintegrating tablet (ODT) formulation of flunarizine. This study will assess two formulations, Formulation A and Formulation B, at dose levels of 2 and 5 mg compared to the reference product, the Sibelium brand of flunarizine 5 mg tablet.
Whilst this is not a first-in-human (FIH) study of flunarizine, which is available in countries outside of Australia and has been studied extensively, it is a FIH study of ASP-001. In this open-label study, 12 participants will be assigned to one of five dosing sequences, in which they will receive a single dose of ASP-001 or Sibelium 5 mg in five separate dosing periods. The study drugs will be:
* Treatment A: ASP-001 Formulation A, 5 mg * Treatment B: ASP-001 Formulation A, 2 mg * Treatment C: ASP-001 Formulation B, 5 mg * Treatment D: ASP-001 Formulation B, 2 mg * Treatment E: Sibelium, 5 mg Each dosing period will be separated by at least a 7-day washout period after the day of dosing. Approximately 14 days after the fifth and final dosing day, participants will return to the site to complete their end of study assessments.
Aboriginal and Torres Strait Islander participants will not be targeted directly; however, they will be permitted to be on-study if they meet all of the eligibility criteria. Participants under the age of 18 will not be permitted on study.
Male or female, ≥18 and ≤65 years of age at screening, with body mass index (BMI) ≥18.5 and ≤32.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
the absence of clinically significant illness and surgery (including abdominal or gastrointestinal surgery that may alter drug absorption) within 4 weeks prior to dosing.
the absence of clinically significant history of neurological (including Parkinson's disease or other extrapyramidal disorders), endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric (including depression), gastrointestinal, renal, hepatic, and metabolic disease.
Non smoker, defined as no use of tobacco or nicotine containing products (including cigarettes, e cigarettes, cigars, pipes, or smokeless tobacco) for at least 6 months prior to screening.
Any clinically significant abnormal finding at physical examination at screening.
PHQ-9 score > 10 at screening or baseline (Day -1).
Clinically significant abnormal laboratory test results or positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody at screening. Any abnormalities or deviations outside the normal ranges for any clinical laboratory testing can be repeated once at the discretion of the investigator and/or designee.
Any of the following laboratory parameters above 1.5× upper limit of normal (ULN) at screening or baseline (Day -1): AST, ALT, direct bilirubin, indirect bilirubin, and total bilirubin. Values over 1.5× ULN may be repeated once for confirmation if the investigator considers it reasonable (e.g., potential elevation due to recent strenuous physical activity).
Sequential
Flunarizine
DrugODT formulation for buccal administration
Flunarizine
Drugoral tablet
Frel
relative bioavailability calculated on the ratio of intervention to control
AUC(0-inf)
area under the concentration-time curve from time zero to infinity (extrapolated)
AUC(0-t)
area under the concentration-time curve from time zero until the last observed concentration
Cmax
maximal observed concentration
Evaluate the safety and tolerability
Measure the incidence and severity of treatment-emergent adverse events
Metabolic Profile
Measure the plasma concentration of liver metabolites M1 (N1 dealkylation), M2 (phenyl oxidation) and M3 (N4 dealkylation)
Dose Proportionality
Measure plasma flunarizine concentrations of 2 mg and 5 mg for each ASP-001 ODT formulation and model for dose response
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