Clinical trial NCT02963116: A Study to Estimate the Effect of AZD5718 on the Pharmacokinetics (What Does the Body Does to the Drug) of Rosuvastatin to Measure the Relative Bioavailability (the Extent to Which a Drug or Other Substance Becomes Available to the Body) of AZD5718 Oral Suspension vs AZD5718 Immediate Release Tablet
Official title: A Randomized, 5-Period, 5-Treatment, Single-Dose, Open-Label, Single-Center, Crossover Study to Estimate the Effect of AZD5718 on the Pharmacokinetics of Rosuvastatin, and to Assess the Relative Bioavailability of AZD5718 Oral Suspension vs AZD5718 IR Tablet Formulation and the Food Effect of AZD5718.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: High Risk Coronary Artery Disease
Keywords: Pharmacokinetics (PK)
Bioavailability (BA)
Safety
Tolerability
Healthy Volunteers
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-11-15
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: This study is a randomized, open-label, 5-period, 5-treatment, single-dose, single-center, crossover study to estimate the effect of AZD5718 on the pharmacokinetics (PK) of rosuvastatin, and to assess the relative bioavailability of AZD5718 oral suspension vs AZD5718 immediate release (IR) Tablet Formulation and the Food Effect of AZD5718 in Healthy Volunteers. The study will be performed at a single study center.

Detailed description: The study will comprise:

* A Screening period of maximum 28 days;
* Five treatment periods during which subjects will be resident from the morning on the day before dosing with the IMP (Day -1) until at least 48 hours after dosing; discharge will be on the morning of Day 3, and
* A Follow-up Visit within 7 to 10 days after the last administration of the IMPs.
* There will be a minimum of a 7 days washout between each treatment period.

Each subject will receive 5 treatments. The following treatments will be given:

* Treatment A: 10 mg rosuvastatin tablet alone (fasting state)
* Treatment B: 10 mg rosuvastatin tablet + 200 mg of AZD5718 IR tablet (2 x 100 mg tablet) (fasting state)
* Treatment C: 200 mg of AZD5718 IR tablet (2 x 100 mg tablet) (fasting state)
* Treatment D: 200 mg of AZD5718 oral suspension 50 mg/mL (fasting state)
* Treatment E: 200 mg of AZD5718 IR tablet (2 x 100 mg tablet) (fed state)

Each subject will be involved in the study for approximately 8 weeks.

Eligibility criteria: Inclusion Criteria:

For inclusion in the study, subjects should fulfill the following criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy male and/or female subjects (of non childbearing potential) aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
3. Females must have a negative pregnancy test at the Screening Visit and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria 3.1. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone levels in the postmenopausal range.

   3.2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral ophorectomy or bilateral salpingectomy but excluding bilateral tubal ligation.
4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg, inclusive.
5. Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study.

Exclusion Criteria:

Subjects will not enter the study if any of the following exclusion criteria are fulfilled:

1. History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
2. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at the Screening Visit and/or admission to the study unit as judged by the PI including: - Aminotransferase (ALT) \> upper limit of normal (ULN); - Aspartate aminotransferase (AST) \> ULN; - Total bilirubin (TBL) \> ULN; and - Gamma glutamyl transpeptidase (GGT) \> ULN.
5. Any clinically significant abnormal findings in vital signs at the Screening Visit and/or admission to the study unit, as judged by the PI defined as any of the following: - Systolic BP (SBP) \< 90 mmHg or ≥ 140 mmHg; - Diastolic BP (DBP) \< 50 mmHg or ≥ 90 mmHg; and - Pulse \< 45 or \> 85 beats per minute (bpm).
6. Any clinically significant abnormalities (at the Screening Visit and admission) in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
7. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
8. Subjects with myopathy.
9. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest. Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
10. Plasma donation within 1 month of the Screening Visit or any blood donation/loss more than 500 mL during the 3 months prior to the Screening Visit.
11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5718 and/or rosuvastatin.
12. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the 3 months prior to the Screening Visit.
13. Positive screen for drugs of abuse or cotinine at the Screening Visit or on each admission to the study center or positive screen for alcohol on each admission to the study center.
14. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
15. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
16. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 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. Note: Hormonal replacement therapy is not allowed for females.
17. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
18. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives. 19. Subjects who have previously received AZD5718.

20. Judgment by the PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.

21. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order In addition, the following is considered a criterion for the exclusion from the optional genetic component of the study: 22. Previous bone marrow transplant. 23. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection or previous bone marrow transplant.

Primary outcomes:
measure: Area under plasma concentration-time curve from time zero to infinity (AUC) of Rosuvastatin
timeFrame: Pre-dose, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration [AUC(0-last)] of Rosuvastatin
timeFrame: Pre-dose, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose
measure: Maximum observed plasma concentration (Cmax) of Rosuvastatin
timeFrame: Pre-dose, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose
Secondary outcomes:
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½) of Rosuvastatin -
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose. (Only Treatment A and B)
measure: Time to reach maximum observed plasma concentration (tmax) of rosuvastatin
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose. (Only Treatment A and B)
measure: AUC of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: AUC(0-last) of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: Cmax of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: tmax of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: t½ of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) of AZD5718
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36 and 48 h post-dose (Only Treatment B, C, D, and E)
measure: Adverse events (AEs)
timeFrame: Screening, Day -1 and Days 1 to 3 (treatment periods 1 to 5) and follow up visit (7-10 days post final dose)
measure: Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature)
timeFrame: Screening, Day -1, Pre-dose, 48 h post-dose and Follow-up visit (7-10 days post final dose)
measure: Electrocardiogram (ECG)
timeFrame: Screening, Day -1, Pre-dose, 48 h post-dose and Follow-up visit (7-10 days post final dose)
measure: Physical examination
timeFrame: Screening, Day -1 (brief), 48 h (brief) post-dose
measure: Laboratory assessments (hematology, clinical chemistry and urinalysis).
timeFrame: Screening, Day -1 (only limited clinical laboratory evaluations will be performed), Pre-dose, 48 h post-dose and Follow-up Visit (7-10 days post final dose)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit London
name: Dr. Muna Albayaty, MBChB, MSc, MFPM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ericsson H, Nelander K, Heijer M, Kjaer M, Lindstedt EL, Albayaty M, Forte P, Lagerstrom-Fermer M, Skrtic S. Phase 1 Pharmacokinetic Study of AZD5718 in Healthy Volunteers: Effects of Coadministration With Rosuvastatin, Formulation and Food on Oral Bioavailability. Clin Pharmacol Drug Dev. 2020 Apr;9(3):411-421. doi: 10.1002/cpdd.756. Epub 2019 Dec 2.