The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending oral doses of ASP6282 in healthy male and female subjects. 1 cohort (elderly) receives also a midazolam dosing. This study will also explore the effect of itraconazole (another drug) on the PK of ASP6282, as well as to evaluate the safety and tolerability of ASP6282 alone and in combination with itraconazole in healthy male and female subjects. Also, this study is to evaluate the PD and PK effects of single oral doses of ASP6282 on pilocarpine-induced salivation and pupil diameter in healthy nonelderly male and female subjects.
This study consists of three parts. Part 1 is Single Ascending Dose Including Food Effect and Drug-drug Interaction (DDI) with Itraconazole. There will be a washout between treatment period 1 and 2 in the DDI arm of Part 1; Part 2 is a Multiple Ascending Dose (MAD); Part 3, with a treatment period 1, 2 and 3 is Proof of Pharmacology. There will be a washout between each treatment period
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
116
oral
oral
oral
oral
oral
Site DE49001
Berlin, Germany
Site GB44001
Harrow, United Kingdom
Safety as assessed by adverse events
Time frame: Part 1: up to 10 days; Part 2 up to 18 days
Safety as assessed by vital signs
Vital signs include: blood pressure, pulse rate and body temperature
Time frame: Part 1: up to 10 days; Part 2 up to 18 days
Safety as assessed by safety laboratory tests
Laboratory tests include: hematology, biochemistry and urinalysis
Time frame: Part 1: up to 10 days; Part 2 up to 18 days
Safety as assessed by electrocardiogram (ECG) measurements (Part 1)
ECG measurements include routine ECG
Time frame: From screening to end of study visit (ESV) (up to day 10)
Safety as assessed by continuous cardiac monitoring (Part 1)
12- lead ECG continuous cardiac monitoring, real-time cardiac monitoring (telemetry), cardiac troponin
Time frame: From day 1 up to day 5
Safety as assessed by electrocardiogram (ECG) measurements (Part 2)
ECG measurements include routine 12- lead ECG, cardiac troponin
Time frame: From screening to ESV (Up to day 18)
Safety as assessed by continuous electrocardiogram (ECG) measurements (Part 2)
Twelve lead continuous cardiac monitoring, cardiac troponin
Time frame: From screening up to day 15
Safety as assessed by the Orthostatic challenge test (OCT) (Part 1)
Blood pressure measurement
Time frame: From day -1 up to day 5
Pharmacodynamic parameter salivary secretion at specified timepoints (Part 3)
Measured (mg/min) salivary secretion at specific timepoints
Time frame: Day 1, each treatment period
Pharmacodynamic parameter salivary secretion AUEsal (Part 3)
Area under the effect curve salivary secretion (AUEsal)
Time frame: Day 1, each treatment period
Pharmacodynamic parameter salivary secretion Emax,sal (Part 3)
Maximum pharmacodynamic effect salivary secretion (Emax,sal)
Time frame: Day 1, each treatment period
Pharmacodynamic parameter salivary secretion tmax,sal (Part 3)
Time at maximum concentration salivary secretion (tmax,sal)
Time frame: Day 1, each treatment period
Pharmacokinetics profile of ASP6282 (plasma): AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 1)
Area under the concentration-time curve from the time of dosing extrapolated to time infinity (AUCinf); Area under the concentration-time curve from the time of dosing to the last measurable concentration (AUClast); Maximum concentration (Cmax); Apparent total systemic clearance after extravascular dosing (CL/F); Time prior to the time corresponding to the first measurable (nonzero) concentration (tlag);Time at maximum concentration (tmax); Terminal elimination half-life (t½); Apparent volume of distribution during the terminal elimination phase after extravascular dosing (Vz/F)
Time frame: Day 1 up to Day 5, each treatment period
Pharmacokinetics profile of ASP6282 (urine): Aelast, Aelast%, Aeinf, Aeinf%, CLR (Part 1)
Cumulative amount of study drug excreted into urine from time of dosing up to the collection time of the last measurable concentration (Aelast); Percentage of study drug dose excreted into urine from time of dosing up to the collection time of the last measurable concentration (Aelast%); Cumulative amount of study drug excreted into urine from time of dosing extrapolated to time infinity (Aeinf); Percentage of study drug dose excreted into urine from time of dosing extrapolated to time infinity (Aeinf%); Renal clearance (CLR)
Time frame: Day 1 up to Day 4, each treatment period
Pharmacokinetic parameter of Itraconazole (plasma) Ctrough (Part 1)
DDI arm only. Concentration immediately prior to dosing at multiple dosing (Ctrough)
Time frame: Day 1 up to Day 5, each treatment period
Pharmacokinetics profile of ASP6282 (plasma): AUC24, tlag, AUCtau, CL/F, PTR, Rac(AUC), Cmax, tmax, t½, Vz/F (Part 2)
Area under the concentration-time curve from the time of dosing to 24 hours postdose (AUC24); Area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau); Peak trough ratio (PTR), Accumulation ratio calculated using the area under the concentration-time curve (Rac(AUC))
Time frame: Day 1 up to Day 20
Pharmacokinetics profile of ASP6282 (urine): Aetau, Aetau%, CLR (Part 2)
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Percentage of study drug dose excreted into urine over the time interval between consecutive dosing (Aetau%)
Time frame: Day 14
Pharmacokinetics profile of ASP6282 (plasma): AUC6, AUCinf, AUClast, Cmax, CL/F, tlag, tmax, t½, Vz/F (Part 3)
Area under the concentration-time curve from the time of dosing to 6 hours Postdose (AUC6)
Time frame: Day 1 up to Day 5, per treatment period
Pharmacokinetics profile of Pilocarpine (plasma): AUC6, Cmax, tmax (Part 3)
Time frame: Day 1, per treatment period
Pharmacodynamic profile pupil diameter pupS, AUEpupS, Emax,pupS, tmax,pupS, (Part 1, Part 2)
Part 1: exclusive DDI arm. Pupil diameter, scotopic lighting condition (pupS); Area under the effect curve pupil diameter, scotopic lighting condition (AUEpupS); Maximum pharmacodynamic effect pupil diameter, scotopic lighting condition (Emax,pupS), Time at maximum concentration pupil diameter, scotopic lighting condition (tmax,pupS)
Time frame: Part 1: Day 1; Part 2: Day -1 and Day 14
Pharmacodynamic profile salivary secretion AUEsal, Emax,sal, tmax,sal (Part 1, Part 2)
Part 1: exclusive DDI arm
Time frame: Part 1: Screening and Day 1; Part 2: Day -1 and Day 14
Pharmacodynamic profile of Bond and Lader VAS (Part 1, Part 2)
Visual analogue scale (VAS)
Time frame: Part 1: Day 1; Part 2: Day -1 and Day 14
Safety profile assessed by nature, frequency and severity of adverse events, vital signs, safety laboratory tests and 12 lead ECG (Part 3)
Time frame: Screening, Day -1 and ESV (Day 10)