This study will assess the effect of multiple doses of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) in healthy participants. This study will consist of 2 treatment arms (Treatment Arms A and B) and within each treatment arm, the participants will first be administered the probe substrates (midazolam, rosuvastatin, and digoxin) alone followed by administration of the probe substrates together with AZD5462. The treatment arms differ in the dose of AZD5462 being administered and will be performed sequentially starting with Treatment Arm A (AZD5462 Dose A, high dose treatment arm) and followed by Treatment Arm B (AZD5462 Dose B, low dose treatment arm). Each treatment arm will include 5 periods. Thirty two participants in total (16 participants per treatment arm) will be enrolled to ensure at least 24 evaluable participants (12 participants per treatment arm) at the end of the last treatment period. A follow-up visit at Day 24 (+-1 Day) will be conducted via a phone call.
This is a phase I, single-centre, 2-treatment arm, 5-period, fixed sequence study. The Study Will Comprise of a Screening Period and Five Treatment Periods: * Screening Period (Maximum 28 Days) Participant eligibility will be confirmed during the Screening Visit. * Period 1 (Day 1) Single dose administration of midazolam on Day 1. * Period 2 (Day 2) Single dose administration of rosuvastatin and digoxin on Day 2. There will be a minimum washout period of 3 days between Period 2 and Period 3. * Period 3 (Days 6 to 14) Single dose administration of rosuvastatin and digoxin together with AZD5462 (Treatment Arm A, Dose A; Treatment Arm B, Dose B) on Day 6. AZD5462 will continue to be administered throughout the period including Day 14. * Period 4 (Day 15) Single dose administration of midazolam together with AZD5462 (Treatment Arm A, Dose A; Treatment Arm B, Dose B) at steady state on Day 15. * Period 5 (Days 16 to 18) Single dose administration of rosuvastatin and digoxin together with AZD5462 (Treatment Arm A, Dose A; Treatment Arm B, Dose B) at steady state on Day 16. AZD5462 will continue to be administered on Days 17 and 18. Participants will be resident in the study centre when dosed with probe substrates (midazolam, rosuvastatin, and digoxin) and/or AZD5462 including the washout period between Period 2 and Period 3. Residency will commence on Day -1 and end on Day 20. A follow-up visit at Day 24 (+-1 Day) will be conducted via a phone call.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
32
Treatment Arm A: Participants will receive the IMP, AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin Treatment Arm B: Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin
Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms.
Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.
Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.
Research Site
Brooklyn, Maryland, United States
Area under the concentration-versus-time curve from pre-dose (time 0) extrapolated to infinite time (AUCinf)
The effect of AZD5462 on the AUCinf of oral midazolam, rosuvastatin, and digoxin will be assessed.
Time frame: Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)
Area under the concentration-versus-time curve from pre-dose (time 0) to the time of the last quantifiable concentration (AUClast)
The effect of AZD5462 on the AUClast of oral midazolam, rosuvastatin, and digoxin will be assessed.
Time frame: Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)
Maximum observed serum (peak) drug concentration [Cmax]
The effect of AZD5462 on the Cmax of oral midazolam, rosuvastatin, and digoxin will be assessed.
Time frame: Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)
Time to reach peak or maximum observed concentration or response following drug administration (tmax)
The effect of AZD5462 on the tmax of oral midazolam, rosuvastatin, and digoxin will be assessed.
Time frame: Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)
Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)
The effect of AZD5462 on the t1/2λz of oral midazolam, rosuvastatin, and digoxin will be assessed.
Time frame: Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)
Partial area under the serum concentration time curve from time 0 to time 12 (AUC0-12h)
The AUC0-12h of AZD5462 will be determined.
Time frame: Day 6, and Day 16
Maximum observed serum (peak) drug concentration [Cmax]
The Cmax of AZD5462 will be determined.
Time frame: Day 6, and Day 16
Time to reach peak or maximum observed concentration or response following drug administration (tmax)
The tmax of AZD5462 will be determined.
Time frame: Day 6, and Day 16
Trough plasma exposure of AZD5462 (Ctrough)
Ctrough values of AZD5462 will be determined.
Time frame: Days 14 to 15, and Days 17 to 18
Incidence of Adverse Events (AEs)
The safety and tolerability of AZD5462 alone and in combination with midazolam, rosuvastatin, and digoxin will be examined.
Time frame: From screening (Day -28 to Day -2) to follow-up (Day 20)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.