A Phase I Study to Assess PK of AZD7986 Alone & With Verapamil, Itraconazole or Diltiazem in Healthy Subjects
Condition: Healthy Subjects
Intervention: AZD7986; Verapamil; Itraconazole; Diltiazem
Intervention description: Oral solution, single dose, dilution from concentrate; Extended release tablet for oral use; Oral solution; Extended release capsule
Intervention MeSH terms: Itraconazole; Verapamil; Diltiazem
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Non-randomized; Verapamil; Itraconazole; Diltiazem; Safety; Tolerability; Pharmacokinetics

Summary:

      This is a phase 1, non-randomized, fixed sequence, 3-period, drug-drug interaction study to
      assess the pharmacokinetics (PK) of AZD7986 in healthy subjects when administered alone and
      in combination with multiple doses of verapamil and itraconazole or diltiazem
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of signed and dated, written informed consent prior to any study specific
             procedures.

          2. Healthy male and/or female subjects aged 18 to 55 years (inclusive) with suitable
             veins for cannulation or repeated venepuncture.

          3. Females must have a negative pregnancy test at screening and on admission to the unit,
             must not be lactating and must be of non-childbearing potential, confirmed at
             screening by fulfilling 1 of the following criteria:

             Post-menopausal defined as amenorrhea for at least 12 months or more following
             cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH)
             levels in the post menopausal range(> 40 milli-International unit [mIU]/mL).

             Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
             oophorectomy or bilateral salpingectomy, but not 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.

          6. Hormone replacement therapy is not allowed for females to exclude any drug drug
             interaction between the hormone replacement therapy and AZD7986.

        Exclusion Criteria:

          1. History of any clinically significant disease or disorder which, in the opinion of the
             investigator, 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 (GI), 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 AZD7986.

          4. Any clinically significant abnormalities in clinical chemistry, haematology, or
             urinalysis results, as judged by the investigator.

          5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg),
             hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.

          6. Any clinically significant abnormal findings in vital signs after at least 10 minutes
             of rest, defined as the following:

               -  Systolic blood pressure < 100 mmHg or > 140 mmHg;

               -  Diastolic blood pressure < 50 mmHg or > 90 mmHg; or

               -  Pulse rate < 50 or > 85 beats per minute.

          7. Any clinically important abnormalities in rhythm, conduction or morphology of the
             resting electrocardiogram (ECG) and any clinically important abnormalities in the 12
             Lead ECG as considered by the investigator that may interfere with the interpretation
             of ECG interval measured from the onset of the QRS complex (electrical activity or
             ventricular contraction on the ECG where Q represents the downward deflection, R
             represents upward deflection and S represents a downward one) to the end of the T wave
             corrected for heart rate (QTc) interval changes, including abnormal ST-T-wave
             morphology, particularly in the protocol defined primary lead or left ventricular
             hypertrophy.

          8. Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450
             ms or shortened QTcF < 340 ms or family history of long QT syndrome.

          9. PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there
             is no evidence of ventricular pre-excitation).

         10. PR (PQ) interval prolongation > 200 ms, intermittent second or third degree
             atrioventricular (AV) block (Wenckebach block while asleep is not exclusive), or AV
             dissociation.

         11. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle
             branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms.
             Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of
             e.g., ventricular hypertrophy or pre-excitation.

         12. Known or suspected history of drug abuse, as judged by the investigator.

         13. Current smokers or those who have smoked or used nicotine products within the 3 months
             before screening.

         14. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as
             judged by the investigator.

         15. Positive screen for drugs of abuse or cotinine at screening or on each admission to
             the study centre or positive screen for alcohol on each admission to the study unit.

         16. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as
             judged by the investigator or history of hypersensitivity to drugs with a similar
             chemical structure or class to AZD7986.

         17. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate,)
             as judged by the investigator.

         18. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks
             prior to the first administration of AZD7986.

         19. Use of any prescribed or non-prescribed medication including antacids and other drugs
             for gastric acid-related disorders, 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 AZD7986 or
             longer if the medication has a long half-life.

             Note: Hormonal replacement therapy is not allowed for females.

         20. Plasma donation within 1 month of screening or any blood donation/loss more than 500
             mL during the 3 months prior to screening.

         21. 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 AZD7986 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 dosed in this study or a previous phase
             I study, are not excluded.

         22. Subjects who have previously received AZD7986.

         23. Involvement of any AstraZeneca, PAREXEL or study site employee or their close
             relatives.

         24. Judgment by the investigator 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.

         25. Subjects who cannot communicate reliably with the investigator.

         26. Subjects who are vegans or have medical dietary restrictions.

         27. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship,
             trusteeship, or committed to an institution by governmental or juridical order.

         28. Subject has increased risk of infection:

               -  History and/or presence of tuberculosis (TB); positive result for interferon
                  gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), subjects who have resided
                  in regions where tuberculosis and mycosis are endemic during 90 days before
                  screening, or who intend to visit such a region during the duration of the study
                  i.e., deserts areas, Eastern Europe, Central and South America, Africa except
                  Egypt, Russia, Asia, Indonesia. The test may be repeated if the initial test
                  result is indeterminate.

               -  Oral body temperature of > 37.7°C on Day -1, or as judged by the investigator.

               -  Blood neutrophil count < 1.7 x109/L (Screening and Day -1 morning sample).

               -  Is in high risk-group for HIV infection within the last 6 months (i.e., men who
                  have had unprotected sex with men, women who have had sex without a condom with
                  men who have sex with men, people who have had sex without a condom with a person
                  who has lived or travelled in Africa, people who inject drugs, people who have
                  had sex without a condom with somebody who has injected drugs, people who have
                  caught another sexually transmitted infection, people who have received a blood
                  transfusion while in Africa, Eastern Europe, the countries of the former Soviet
                  Union, Asia or Central and Southern America).

               -  Other latent or chronic infections (e.g., recurrent sinusitis, genital or ocular
                  herpes, urinary tract infection) or at risk of infection (surgery, trauma, or
                  significant infection) within 90 days of screening, or history of skin abscesses
                  within 90 days of screening.

               -  Clinically significant lower respiratory tract infection not resolved within 4
                  weeks prior to screening, as determined by the investigator.

               -  Subjects with active malignancy or neoplastic disease in the previous 5 years
                  other than superficial basal cell carcinoma.

               -  Disease history suggesting abnormal immune function.

               -  Subjects who have received live or live-attenuated vaccine in the 4 weeks prior
                  to dosing.

               -  High-sensitivity C-reactive protein above upper limit of laboratory reference
                  range at screening and on Day -1.

         29. Subjects with a history or signs of current gingivitis/periodontitis or a history or
             current hyperkeratosis of palms and soles will be excluded. (Due to the fact that many
             subjects lacking functional DPP1 enzyme have been described to have periodontitis and
             palmoplantar hyperkeratosis.)

         30. Subjects with total urinary protein/urine creatinine ratio outside the normal range.

         31. Drugs affecting CYP3A4 should be refrained from use for 3 weeks prior to study
             commencement and thereafter until study completion.

             In addition, the following is considered a criterion for the exclusion from the
             optional genetic component of the study:

         32. History of bone marrow transplant

         33. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
             genetic sample collection.

         34. Hypersensitivity to the verapamil or to any of the excipients.

         35. History of serious cardiac events such as myocardial infarction.

         36. History of sino-atrial block; sick sinus syndrome; chronic or uncompensated heart
             failure (including left ventricular heart failure).

         37. History of atrial flutter, atrial fibrillation or Wolff-Parkinson-White syndrome.

         38. Known hypersensitivity to diltiazem or to any of the excipients.

         39. Known hypersensitivity to itraconazole or to any of the excipients.

         40. Elevated or abnormal liver enzymes or active liver disease, or who have experienced
             liver toxicity with other drugs.