Drug Interaction Study of Pyronaridine-artesunate & Metoprolol, & Redosing Study of Pyronaridine-artesunate
Condition: Malaria
MeSH terms: Malaria
Intervention: Metoprolol and pyronaridine-artesunate; pyronaridine-artesunate
Intervention description: On Day 1, subjects will receive a single oral 100 mg dose of metoprolol tartrate. On Day 8 and Day 9, subjects will receive a once daily oral dose of pyronaridine-artesunate as follows:
55 - < 65 kg: 3 tablets (180:60 mg pyronaridine:artesunate)
≥ 65 kg: 4 tablets (180:60 mg pyronaridine:artesunate)
On Day 10, a 100 mg dose of metoprolol will be coadministered with pyronaridine-artesunate at the above dose.
On Days 98 - 100, subjects will receive pyronaridine-artesunate once daily at the same dose described above. Followed by a 40 day follow-up period.; On Days 1 to 3, subjects will receive 3 days of pyronaridine-artesunate as follows:
55 - < 65 kg: 3 tablets (180:60 mg pyronaridine:artesunate)
≥ 65 kg: 4 tablets (180:60 mg pyronaridine:artesunate)
On Days 61 to 63, subjects will be redosed with a 3 day course of pyronaridine-artesunate at the above dose.
Followed by a 40 day follow-up period.
Intervention MeSH terms: Artesunate; Pyronaridine; Pyronaridine tetraphosphate, artesunate drug combination; Metoprolol
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: pyronaridine artesunate (Pyramax); artemisinin based combination therapy (ACT); metoprolol; drug-drug interaction study; redosing study

Summary:

      The primary objective of the drug-drug interaction study is to evaluate any drug interaction
      between the CYP2D6 substrate metoprolol and pyronaridine-artesunate in healthy volunteers.

      The primary objective of the pyronaridine-artesunate redosing study is to determine the
      safety of redosing a 3-day regimen of pyronaridine-artesunate following 60 or 90 days in
      healthy volunteers.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female subjects between the ages of 18 and 55 years with a body weight between
             50 and 90 kg and a body mass index calculated using Quetelet's Index - weight
             (kg)/height2 (m2) between 18.5-30.0

          2. Signed and dated a written informed consent form before undergoing any study related
             activities

          3. Medically normal subjects with no significant abnormal findings at the screening
             physical examination as evaluated by the investigator

          4. Strictly normal values of alanine aminotransferase, aspartate aminotransferase, and
             total bilirubin and normal or abnormal and clinically insignificant results of the
             other blood and urine laboratory parameters at screening.

          5. Female subjects of non-childbearing potential (i.e. physiologically incapable of
             becoming pregnant, including any female who was post-menopausal (i.e. one year without
             menses) or who has undergone sterilization (via hysterectomy or bilateral tubal
             ligation)

          6. Female subjects of childbearing potential with a negative urine pregnancy test at
             screening confirmed at Day -1 by a serum pregnancy test and who agreed to one of the
             following methods:

               -  Double barrier method of contraception for 2 weeks before first study drug
                  administration and throughout the entire study follow up period

               -  Partner(s) who had undergone vasectomy and has been negative for sperm for at
                  least 6 months

          7. The ability to understand the requirements of the study and willingness to comply with
             all study procedures

        Exclusion Criteria:

          1. Known history or evidence of clinically significant disorders such as cardiovascular
             (including arrhythmia, acute corrected QT interval greater or equal to 450
             milliseconds), respiratory (including active tuberculosis), hepatic, renal,
             gastrointestinal, immunological (including active HIV-AIDS), neurological (including
             auditory), endocrine, infectious, malignancy, psychiatric or other abnormality
             (including head trauma)

          2. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or
             artesunate or other artemisinins or metoprolol.

          3. Other contraindications to pyronaridine use

          4. Other contraindications to metoprolol use including second or third degree
             atrioventricular block, heart rate below 50 beats per minute, uncompensated heart
             failure or need for treatment with inotropic agents, clinically apparent hypotension,
             sinus bradycardia or sick sinus syndrome, peripheral arterial disease,
             pheochromocytoma, asthma, chronic obstructive pulmonary disease, depression and any
             other condition with in the opinion of the Investigator may be worsened by
             administration of metoprolol.

          5. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or
             Hepatitis C antibody (HCV Ab)

          6. Seropositive HIV antibody

          7. Previous participation in any clinical study with pyronaridine:artesunate (Pyramax)

          8. Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day)

          9. Known or suspected alcohol abuse or illicit drug use 10 years before the study start
             or positive findings on urine drug screen

         10. Intake of alcoholic beverages within 72 hours before study drug administration or
             caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 48
             hours before study drug administration

         11. Gilbert's disease

         12. Administration of any systemic medication or herbal product within 14 days before the
             first dose of study drug. If the investigator considers that the specific product
             would not interfere with the safety of the subject or the objectives of the study,
             topical treatments as well as vitamins and mineral supplements not containing other
             substances are allowed until 4 days before each dose. Ibuprofen at doses of at most
             1200 mg per day for no more than 3 consecutive days or 6 non-consecutive days is
             allowed until 24h before the first dose of study drug.

         13. Plasma donation 3 months before the study start

         14. Blood donation of 500 mL or more 3 months before the study start

         15. Participation in any clinical study in last 3 months