Pharmacokinetic Analysis
Conditions
Brief summary
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.
Interventions
DRUGFlunarizine
ODT formulation for buccal administration
Sponsors
Aspartes Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
5-way, randomized, open-label, sequential single administration under fasting conditions
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. 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. 2. Healthy as defined by: 1. the absence of clinically significant illness and surgery (including abdominal or gastrointestinal surgery that may alter drug absorption) within 4 weeks prior to dosing. 2. 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. 3. 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. 4. Female participants of non-childbearing potential must be: 1. post-menopausal (spontaneous amenorrhea for at least 12 months prior to dosing) with confirmation by documented follicle stimulating hormone (FSH) levels ≥40 mIU/mL; or 2. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) or having had a tubal ligation performed at least 3 months prior to dosing. 5. Sexually active female participants of childbearing potential and non-sterile male participants must be willing to use an acceptable contraceptive method throughout the study as detailed in section 7.1. 6. Willing to take off dentures or mouth piercing at the time of dosing. 7. Able to understand the study procedures and provide signed informed consent to participate in the study.
Exclusion criteria
1. Any clinically significant abnormal finding at physical examination at screening. 2. PHQ-9 score \> 10 at screening or baseline (Day -1). 3. 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. 4. 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). 5. History of clinically significant liver disease, impaired synthetic liver function, or jaundice. Resolved childhood jaundice is not exclusionary. 6. Value of creatinine clearance (CrCl) \<60 mL/min, as estimated by the Cockcroft-Gault equation. 7. Positive pregnancy test or lactating female participant. 8. Positive urine drug screen, urine cotinine test, or alcohol breath test. 9. Known allergic reactions to flunarizine or other related drugs, or to any excipient in the formulation. 10. Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 40 or over 90 mmHg, or heart rate less than 40 or over 100 bpm) at screening. Any abnormalities or deviations outside the normal range for vital signs and ECG can be repeated at the discretion of the investigator and/or designee. 11. History of drug abuse within 1 year prior to screening or recreational use of marijuana within 1 month, or use of cocaine, phencyclidine \[PCP\], crack, opioid derivatives (including heroin) or amphetamine derivatives within 3 months prior to screening. 12. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeds 14 standard drinks for females or 21 standard drinks for males of alcohol per week (1 standard drink = 375 mL of mid-strength beer 3.5% alcohol/volume, 100 mL of wine 13.5% alcohol/volume, or 30 mL of distilled alcohol 40% alcohol/volume). 13. Use of medications within the the following timeframes prior to dosing: * Depot injections or drug implants: within 3 months. * Strong CYP2D6 inhibitors or strong CYP inducers such as fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, terbinafine, mirabegron, darifenacin, rifampin, carbamazepine, phenytoin, phenobarbital, and St. John's wort: within 30 days. * Prescription medications: within 14 days. * Vaccines (including COVID 19 vaccines): within 14 days. * Over the counter (OTC) medications and natural health products (herbal, homeopathic, probiotics, vitamins, minerals, amino acids, essential fatty acids, protein supplements): within 7 days, except occasional paracetamol up to 2 g/day. No concomitant medications are permitted during the study except those required for AE management or those specifically exempted by the Investigator and/or designee as unlikely to affect PK or safety. 14. Concomitant participation in an interventional or observational trial, or administration of an investigational device or non-biological drug within 30 days (or 5 half-lives, whichever is longer) prior to dosing, or administration of an investigational biological drug within 90 days (or 5 half-lives, whichever is longer) prior to dosing. 15. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing. 16. Hemoglobin \<125 g/L for males and \<110 g/L for females. One repeat test is permitted at the discretion of the Investigator and/or designee. 17. Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the mouth or tongue that in the opinion of the investigator and/or designee would be likely to interfere with successful completion of the dosing procedure. 18. Any reason which, in the opinion of the Investigator and/or designee, would prevent the participant from participating in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frel | Through Study Day 5 for each intervention and control | relative bioavailability calculated on the ratio of intervention to control |
| AUC(0-inf) | Through Study Day 5 for each intervention and control | area under the concentration-time curve from time zero to infinity (extrapolated) |
| AUC(0-t) | Through Study Day 5 for each intervention and control | area under the concentration-time curve from time zero until the last observed concentration |
| Cmax | Through Study Day 5 for each intervention and control | maximal observed concentration |
| Tmax | Through Study Day 5 for each intervention and control | time when the maximal concentration is observed |
| T½ el | Through Study Day 5 for each intervention and control | terminal elimination half-life |
| Kel | Through Study Day 5 for each intervention and control | terminal elimination rate constant |
| Cl/F | Through Study Day 5 for each intervention and control | Apparent clearance |
| Vz/F | Through Study Day 5 for each intervention and control | apparent volume of distribution |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the safety and tolerability | Throughout the study period | Measure the incidence and severity of treatment-emergent adverse events |
| Metabolic Profile | Through Study Day 5 for each intervention and control | Measure the plasma concentration of liver metabolites M1 (N1 dealkylation), M2 (phenyl oxidation) and M3 (N4 dealkylation) |
| Dose Proportionality | Through Study Day 5 for each intervention and control | Measure plasma flunarizine concentrations of 2 mg and 5 mg for each ASP-001 ODT formulation and model for dose response |
Contacts
CONTACTPaul Glidden, PhD
CONTACTDenny Medjedovic
PRINCIPAL_INVESTIGATORPeter Schrader, MBBS, FRACP
Linear Clinical Research
Outcome results
None listed