Drug Interaction Study of Pyronaridine-artesunate & Metoprolol, & Redosing Study of Pyronaridine-artesunate

Inclusion Criteria

• 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
• Signed and dated a written informed consent form before undergoing any study related activities
• Medically normal subjects with no significant abnormal findings at the screening physical examination as evaluated by the investigator
• 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.
• 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)
• 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
• The ability to understand the requirements of the study and willingness to comply with all study procedures

Exclusion Criteria

• 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)
• Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins or metoprolol.
• Other contraindications to pyronaridine use
• 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.
• Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
• Seropositive HIV antibody
• Previous participation in any clinical study with pyronaridine:artesunate (Pyramax)
• Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day)
• Known or suspected alcohol abuse or illicit drug use 10 years before the study start or positive findings on urine drug screen
• 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
• Gilbert's disease
• 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.
• Plasma donation 3 months before the study start
• Blood donation of 500 mL or more 3 months before the study start
• Participation in a