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

Study Overview
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Brief Summary
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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.

Detailed Description
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This was a phase I, open-label, randomised, 2-arm parallel group study in healthy subjects. The study population will include 44 healthy subjects (22 per treatment arm), comprising male and female adults (18-55 years) of any ethnic origin. Subjects will be randomised to either Arm A or Arm B. Arm A will evaluate pyronaridine-artesunate interference on metoprolol pharmacokinetics (PK) and the effect of a 90-day (±7 days) redosing interval on the safety profile of pyronaridine-artesunate. Arm B will evaluate the effect of a 60-day (±7 days) redosing interval on the safety profile of pyronaridine-artesunate. Screening will be performed in the 14-day period prior to the first dose. In Arm A, each subject will partake in 3 inpatients periods between: Days -1 to 2, Days 7 to 11, and Days 97 to 101, with dosing on Days 1, 8 to 10, and 98 to 100. In Arm B, each subject will partake in 2 inpatient periods: Days -1 to 4 and Days 60 to 64, with dosing on Days 1 to 3 and 61 to 63. Subjects will be considered to have completed the study at Day 140 (Arm A) or at Day 103 (Arm B). Any adverse event ongoing at the time of study completion will be followed until resolution unless no further change is expected according to the investigator.

Official Title
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Open-label, Drug Interaction Study of Pyronaridine-artesunate and Metoprolol in Healthy Volunteers and Pyronaridine-artesunate Redosing Study in Healthy Volunteers

Conditions
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Malaria

Intervention / Treatment
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* Drug: Metoprolol and pyronaridine-artesunate
* Drug: pyronaridine-artesunate


Participation Criteria
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Eligibility Criteria
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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 any clinical study in last 3 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: metoprolol and pyronaridine-artesunate 90-day redosing<br>Subjects will take 1 day of metoprolol followed by a 7 day wash out period, then 2 days of pyronaridine-artesunate followed by 1 day of pyronaridine-artesunate + metoprolol, followed by a 87 day follow-up period. Subjects will then receive pyronaridine-artesunate once daily for 3 days followed by a 40 day follow-up period. | Drug: Metoprolol and pyronaridine-artesunate<br>* 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.<br>|
| Active Comparator: Arm B: pyronaridine-artesunate 60-day redosing<br>Subjects will take pyronaridine-artesunate once daily for 3 days, followed by a 57 day follow-up period. Subjects will then take pyronaridine-artesunate once daily for 3 days followed by a 40 day follow-up period. | Drug: pyronaridine-artesunate<br>* 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.<br>* Other names: Pyramax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm A Pharmacokinetic Parameters of Metoprolol & α-hydroxymetoprolol: Area Under Curve (AUC)0-t, AUC0-∞ | AUC0-t & AUC0-∞ of Metoprolol & α-hydroxymetoprolol for Period 1 (metoprolol alone) & Period 2 (pyronaridine-artesunate with metoprolol) Abbreviations: AUC = area under the concentration-time curve; AUC0-t = AUC from Hour 0 to the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn; AUC0-∞ = AUC from Hour 0 to infinity | Plasma samples taken predose and following metoprolol dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose on Days 1 & 10 | 
| Arm A Pharmacokinetics Parameters of Metoprolol & α-hydroxymetoprolol: Tmax | tmax of Metoprolol & α-hydroxymetoprolol for Period 1 (metoprolol alone) & Period 2 (pyronaridine-artesunate with metoprolol) Abbreviations: tmax = time to maximum observed concentration. | Plasma samples taken predose and following metoprolol dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose on Days 1 & 10 | 
| Arm A Pharmacokinetics Parameters of Metoprolol & α-hydroxymetoprolol: t1/2 | t1/2 of Metoprolol & α-hydroxymetoprolol for Period 1 (metoprolol alone) & Period 2 (pyronaridine-artesunate with metoprolol) Abbreviations: t1/2 = apparent terminal phase half-life | Plasma samples taken predose and following metoprolol dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose on Days 1 & 10 | 
| Arm A Pharmacokinetics Parameters of Metoprolol & α-hydroxymetoprolol: Cmax | Cmax of Metoprolol & α-hydroxymetoprolol for Period 1 (metoprolol alone) & Period 2 (pyronaridine-artesunate with metoprolol) Abbreviations: Cmax = maximum peak observed concentration | Plasma samples taken predose and following metoprolol dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose on Days 1 & 10 | 
| World Health Organization (WHO) Treatment Emergent Adverse Events | To assess the safety of redosing a 3-day regimen of pyronaridine-artesunate. Grade 1: mild adverse event Grade 2: moderate adverse event Grade 3: severe and undesirable adverse event Grade 4: life threatening adverse event Grade 5: fatal adverse event resulting in death | 140 days | 
| Non-WHO Listed Treatment Emergent Adverse Events | To assess the safety of redosing a 3-day regimen of pyronaridine-artesunate | 140 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pyronaridine artesunate (Pyramax), artemisinin based combination therapy (ACT), metoprolol, drug-drug interaction study, redosing study