A Single and Multiple Ascending Dose Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD2389 in Healthy Participants
Study Details
Study Description
Brief Summary
This study will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD2389 following single and multiple dose administration (SAD/MAD) to healthy participants.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a Phase I, First In Human (FIH), randomized, single-blind, placebo-controlled, single and multiple ascending dose study in healthy male and/or female participants of non-childbearing potential including healthy participants of Chinese and Japanese ethnicity performed at a single center.
The study consists of 2 parts: Part A and Part B. 72 participants have been planned for Part A and 32 participants for Part B.
Each participant in Part A will be involved in the study for up to 6 weeks, and each participant in Part B will be involved in the study for up to 8 weeks.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1: Part A1 - AZD2389 dose 1/placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 2: Part A1 - AZD2389 dose 2/placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 3: Part A1 - AZD2389 dose 3 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 4: Part A1 - AZD2389 dose 4 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 5: Part A1 - AZD2389 dose 5 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 6: Part A2 - AZD2389 dose 6 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 7: Part A2 - AZD2389 dose 7 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 8: Part A2 - AZD2389 dose 8 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 9: Part A3 - AZD2389 dose 9 /placebo oral administration A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 10: Part B1 - AZD2389 dose 10 /placebo oral administration A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 11: Part B1 - AZD2389 dose 11 /placebo oral administration A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 12: Part B1 - AZD2389 dose 12 /placebo oral administration A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
| Experimental: Cohort 13: Part B2 - AZD2389 dose 13 /placebo oral administration A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo. |
Drug: AZD2389
Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.
Drug: Placebo
Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
|
Outcome Measures
Primary Outcome Measures
- Part A (SAD): Number of participants with adverse events (AE) and serious adverse events (SAE) [Day ≤ -28 (Only SAE), Day -1 (Only SAE), Days 1 and 2, Day 8 Post-dose (± 1 day)]
To assess the safety and tolerability of AZD2389 following oral administration of single ascending doses in healthy participants, including Japanese and Chinese participants.
- Part B (MAD): Number of participants with AE and SAE [Day ≤ -28 (Only SAE), Day -1 (Only SAE), Days 1 to 12, Day 17 (± 1 day)]
To assess the safety and tolerability of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
Secondary Outcome Measures
- Part A (SAD): Plasma concentrations of AZD2389 [Day 1 and Day 2]
To characterize the plasma concentration of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Urine concentrations of AZD2389 [Day 1 and Day 2]
To characterize the urine concentration of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Terminal rate constant (λz) [Day 1 and Day 2]
To characterize the λz of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [Day 1 and Day 2]
To characterize the Ae(t1-t2) of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Area under plasma concentration time curve from zero to infinity (AUCinf) [Day 1 and Day 2]
To characterize the AUCinf of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Dose normalized AUCinf (AUCinf/D) [Day 1 and Day 2]
To characterize the AUCinf/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Area under concentration curve from time 0 to the last quantifiable concentration (AUClast) [Day 1 and Day 2]
To characterize the AUClast of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Dose normalized AUClast (AUClast/D) [Day 1 and Day 2]
To characterize the AUClast/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Apparent total body clearance of drug (CL/F) [Day 1 and Day 2]
To characterize the CL/F of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Maximum observed plasma (peak) drug concentration (Cmax) [Day 1 and Day 2]
To characterize the Cmax of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Dose normalized Cmax (Cmax/D) [Day 1 and Day 2]
To characterize the Cmax/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Renal clearance (CLR) [Day 1 and Day 2]
To characterize the CLR of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [Day 1 and Day 2]
To characterize the fe(t1-t2) of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Mean residence time (MRTinf) [Day 1 and Day 2]
To characterize the MRTinf of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Apparent terminal elimination half-life (t½λz) [Day 1 and Day 2]
To characterize the t½λz of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Time of last quantifiable concentration (tlast) [Day 1 and Day 2]
To characterize the tlast of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Time to reach peak or maximum observed concentration (tmax) [Day 1 and Day 2]
To characterize the tmax of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Apparent volume of distribution based on the terminal phase (Vz/F) [Day 1 and Day 2]
To characterize the Vz/F of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part A (SAD): Change in PD biomarkers over time [Day 1 and Day 2]
To characterize the percentage change in PD biomarkers over time compared to baseline of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.
- Part B (MAD): Plasma concentrations of AZD2389 [Day 1 to Day 12]
To characterize the plasma concentration of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Urine concentrations of AZD2389 [Day 1 and Days 10 to 12]
To characterize the urine concentration of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Terminal rate constant (λz) [Day 1 to Day 12]
To characterize the λz of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] [Day 1 and Days 10 to 12]
To characterize the Ae(t1-t2) of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Area under concentration curve from time 0 to the last quantifiable concentration (AUClast) [Day 1 to Day 12]
To characterize the AUClast of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Area under the concentration-time curve in the dose interval (AUCtau) [Day 1 to Day 12]
To characterize the AUCtau of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Dose normalized AUCtau (AUCtau/D) [Day 1 to Day 12]
To characterize the AUCtau/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Dose normalized AUClast (AUClast/D) [Day 1 to Day 12]
To characterize the AUClast/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Apparent total body clearance of drug (CL/F) [Day 1 and Days 10 to 12]
To characterize the CL/F of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Renal clearance (CLR) [Day 1 and Days 10 to 12]
To characterize the CLR of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Maximum observed plasma (peak) drug concentration (Cmax) [Day 1 to Day 12]
To characterize the Cmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Dose normalized Cmax (Cmax/D) [Day 1 to Day 12]
To characterize the Cmax/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Observed lowest concentration before the next dose is administered(Ctrough) [Day 1 to Day 12]
To characterize the Ctrough of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)] [Day 1 and Days 10 to 12]
To characterize the fe(t1-t2) of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Accumulation ratio for AUC (Rac AUC) [Day 1 to Day 12]
To characterize the Rac AUC of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Accumulation ratio for Cmax (Rac Cmax) [Day 1 to Day 12]
To characterize the Rac Cmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Time to reach peak or maximum observed concentration (tmax) [Day 1 to Day 12]
To characterize the tmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Apparent terminal elimination half-life (t½λz) [Day 1 to Day 12]
To characterize the t½λz of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Apparent volume of distribution based on the terminal phase (Vz/F) [Day 1 to Day 12]
To characterize the Vz/F of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
- Part B (MAD): Change in PD biomarkers over time [Days 1, 2, 4, 8, and 10]
To characterize the percentage change in PD biomarkers over time compared to baseline of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy male and female (of non-childbearing potential) participants with suitable veins for cannulation or repeated venipuncture.
-
Females must have a negative pregnancy test must not be lactating and must be non-childbearing potential, confirmed by post-menopausal defined as amenorrhea for at least 12 months; documentation of irreversible surgical sterilization.
-
Sexually active fertile male participants and their female partners of childbearing potential must be willing to use highly effective contraception from the first day of dosing until 3 months after the last dose of IMP.
-
Have a BMI between 18 and 32 kg/m2 inclusive and weigh at least 50 kg, at the Screening Visit.
-
For the healthy Japanese cohorts (Parts A2 and B2): healthy participants are to beJapanese (eg, natives of Japan or Japanese Americans), defined as having both parents and 4 grandparents who are Japanese. This includes healthy second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.
-
For the healthy Chinese cohort (Part A3): healthy participants are to be Chinese defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
Exclusion Criteria:
-
History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
-
History of chronic haematologic disease.
-
Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
-
Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results
-
Any positive result on Screening for serum Hepatitis B surface antigen (HBsAg), hepatitis C antibody and Human immunodeficiency virus (HIV).
-
Any clinically important abnormalities in rhythm, conduction or morphology of the resting Electrocardiogram (ECG) and any clinically important abnormalities in the 12 lead ECG.
-
Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the investigator or any participant (male or female) who consumes more than one standard alcoholic drink per day on a regular basis in the 6 months prior to screening and as judged by the investigator (a standard drink is defined as 12 fl oz of beer, 5 fl oz of wine or 1.5 fl oz of distilled spirits), ), and/or a positive screen for alcohol at Screening or on each admission to the Clinical Unit.
-
Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the previous 3 months.
-
History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD2389.
-
Excessive intake of caffeine containing drinks or food
-
Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
-
Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen [up to 2 g/day]), herbal remedies, mega dose vitamins (intake of > 20 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half life.
-
Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to the Screening Visit.
-
History of coagulation or bleeding disorders or use of anti-platelets/anti-coagulants during the 3 months prior to the Screening Visit, as judged by the investigator.
-
History of hypersensitivity as judged by the investigator, to drugs with a similar chemical structure or class.
-
History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, or clinically significant new or healing wounds in areas of the body not always covered by clothing such as face, forearm, and lower leg, as judged by the investigator.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Glendale | California | United States | 91206 |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D7930C00001