Drug Interaction Study of Pyronaridine-artesunate and Metoprolol and Pyronaridine-artesunate Re-dosing Study in Healthy Volunteers

This study has been completed.
Sponsor:
Collaborator:
Shin Poong Pharmaceuticals
Information provided by (Responsible Party):
Medicines for Malaria Venture
ClinicalTrials.gov Identifier:
NCT01523002
First received: January 27, 2012
Last updated: January 25, 2013
Last verified: January 2012
  Purpose

Pyronaridine: artesunate (Pyramax) is an antimalarial fixed-dose combination therapy which has been demonstrated to be well tolerated and effective treatment in patients with Plasmodium falciparum and vivax malaria.

This open-label Phase I study has two parts: a drug-drug interaction part intended to investigate the interaction of Pyramax in the pharmacokinetics of the CYP2D6 probe metoprolol and a re-dosing evaluation part intended to investigate the differences on the changes in liver enzymes induced by Pyramax in a first and in a second treatment course and the effect of the redosing interval on the changes in liver enzymes induced by Pyramax in a first and in a second treatment course.


Condition Intervention Phase
Malaria
Drug: Metoprolol and Pyronaridine : artesunate
Drug: pyronaridine:artesunate
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label, Drug Interaction Study of Pyramax (Pyronaridine:Artesunate) and Metoprolol in Healthy Volunteers and Pyramax Re-dosing Study in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Medicines for Malaria Venture:

Primary Outcome Measures:
  • Profile of Pharmacokinetics [ Time Frame: 140 days ] [ Designated as safety issue: No ]

    Area Under Curve (AUC)0-t, AUC0-∞, Cmax, Tmax, and halflife.

    Plasma samples for determination of metoprolol and alphahydroxymetoprolol: pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4,6, 8, 10, 12, and 24 h post-dose.

    Plasma samples for determination of artesunate and dihydroartemisinin: pre-dose and 1, 3, and 6 h post-dose.

    Blood samples for determination of pyronaridine:pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h and 2, 3, 5, 12, 19, 26, 33, and 40 days.


  • Safety of re-treatment [ Time Frame: 140 days ] [ Designated as safety issue: Yes ]

    Pyramax Re-dosing sub-study (Arm A and Arm B):Peak ALT and peak AST values following the first and the second three day Pyramax administration.

    Safety assessments include monitoring of:

    Adverse events, Laboratory parameters, Vital signs, clinical signs and symptoms and physical examination, including changes from baseline, ECG evaluation.



Enrollment: 56
Study Start Date: January 2012
Study Completion Date: October 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A: Metoprolol DDI and Pyramax 90-day re-dosing
Subjects will take 1 day of metoprolol followed by a 7 day wash out period; then 2 days of Pyramax followed by 1 day of Pyramax + metoprolol and then a 87 day follow-up period. Subjects will then receive Pyramax once daily for three days followed by a 40 day follow-up period and a study completion evaluation.
Drug: Metoprolol and Pyronaridine : artesunate

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 Pyramax 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 Pyramax at the above dose.

On Days 98 - 100, subjects will receive Pyramax once daily at the same dose described above.

Active Comparator: Arm B: Pyramax 60-day re-dosing
Subjects will take Pyramax once daily for 3 days, followed by a 57 day follow-up period. Subjects will then take Pyramax once daily for 3 days followed by a 40 day follow-up period.
Drug: pyronaridine:artesunate

In the first period, subjects will receive 3 days of Pyramax as follows:

55 - < 65 kg: 3 tablets (180:60 mg pyronaridine:artesunate)

≥ 65 kg: 4 tablets (180:60 mg pyronaridine:artesunate) followed by a 57 day follow-up period. In the second period, subjects will receive 3 days of Pyramax at the dose described above.


Detailed Description:

Healthy subjects will be randomised to either arm A (sequential metoprolol single dose and Pyramax 3 days course + metoprolol on the last day starting 7 days after Pyramax single dose followed by Pyramax redosing with another 3 days course 90 days later) or arm B (2 courses of 3-days Pyramax separated by 60 days). Each arm will include 22 subjects.

Subjects will be followed for tolerability and pharmacokinetics for 42 days following each start of Pyramax dosing period.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 ALT, AST, 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 QTc interval greater or equal to 450 mseconds), 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01523002

Locations
Switzerland
Covance Clinical Research Unit AG
Allschwil, Basel, Switzerland, 4123
Sponsors and Collaborators
Medicines for Malaria Venture
Shin Poong Pharmaceuticals
Investigators
Principal Investigator: Rolf Pokorny, MD, MSc Covance Research Unit AG
  More Information

No publications provided

Responsible Party: Medicines for Malaria Venture
ClinicalTrials.gov Identifier: NCT01523002     History of Changes
Other Study ID Numbers: SP-C-014-11
Study First Received: January 27, 2012
Last Updated: January 25, 2013
Health Authority: Switzerland: Swissmedic

Additional relevant MeSH terms:
Metoprolol
Metoprolol succinate
Pyronaridine
Artesunate
Artemisinins
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Amebicides

ClinicalTrials.gov processed this record on September 30, 2014