Clinical trial NCT01156389: Pyronaridine Artesunate-Ritonavir Drug-drug Interaction Study
Official title: Open-label, Randomised, Drug Interaction Study of Pyramax (Pyronaridine Artesunate) and the Protease Inhibitor Ritonavir in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria
Keywords: malaria
artemisinin-based combination therapy (ACT)
antimalarial
pyronaridine artesunate (Pyramax)
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Shin Poong Pharmaceuticals
First posted: 2010-07-02
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to determine any drug interaction between the antimalarial Pyramax (pyronaridine artesunate) and the protease inhibitor ritonavir in healthy subjects. The secondary objective of the study is to assess further the safety of Pyramax in this setting.

Detailed description: This is a phase I, open label, randomized study to determine any drug interaction between Pyramax (pyronaridine/artesunate) and the protease inhibitor ritonavir in healthy volunteers. A total of 34 healthy volunteers (17 per treatment arm) will be enrolled in the study so that at least 30 (15 per treatment arm) will complete it. Subjects will be randomly assigned in a 1:1 ratio to receive either ritonavir (100 mg) twice daily for 17 days from Day 1-17 plus Pyramax (180:60 mg) once daily for 3 days from Day 8-10 in Arm A or pyronaridine/artesunate (180:60 mg) alone once daily for 3 days from Day 1-3 in Arm B.

Subjects will come to the clinic the evening before first dosing of Pyramax / ritonavir. If enrolled, and according to the treatment arm, subjects will stay in the clinic and attend subsequent visits as follows:

Arm A:

* Inpatient day -1 (evening) to day 17
* Ambulatory clinic visit once daily (morning) on day 22, 29, 36, 43 and 50 (end of study visit)

Arm B:

* Inpatient day -1 (evening) to day 4 (morning),
* Ambulatory clinic visit once daily (morning) on Day 5, 6, 8, 15, 22, 29, 36, and 43.(end of study visit) The subjects will be evaluated for pharmacokinetic parameters and safety/tolerability.

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)/height (m2) between 18.5-30.0
2. Signed and dated a written informed consent form (ICF) before undergoing any study related activities, including discontinuation of any prohibited medications
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 bilirubin and normal or abnormal and clinically insignificant results (if agreed by the Investigator and the Sponsor on a case by case evaluation) 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 and a negative plasma pregnancy test prior to inclusion 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 clinical abnormality
2. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins or ritonavir
3. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab)
4. Seropositive HIV antibody
5. Previous participation in any clinical study with Pyramax
6. Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day)
7. Known or suspected alcohol abuse or illicit drug use in the last 10 years before the study start or positive findings on urine drug screen
8. Intake of grapefruit and grapefruit juice alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 48 hours before study drug administration
9. Use of over-the-counter (OTC) medications, including vitamins, analgesics, or antacids, 1 week before the study start
10. Use of prescription medications 14 days before the study start or required chronic use of any prescription medication
11. Use of enzyme-altering agents (e.g., barbiturates, phenothiazines, cimetidine, etc.) within 30 days or 5 half lives, whichever the longer, before the study start
12. Plasma donation 1 month before the study start
13. Blood donation of 450 mL or more in the last 3 months before the study start
14. Participation in any clinical study in last 2 months

Primary outcomes:
measure: Pharmacokinetics Analysis: Half-life, Tmax
timeFrame: Until Day 50 for Arm A and until Day 43 for Arm B
measure: Pharmacokinetics Analysis: Cmax
timeFrame: Until Day 50 for Arm A and until Day 43 for Arm B
measure: Pharmacokinetics Analysis: AUC0-tau, AUC0-∞
timeFrame: Until Day 50 for Arm A and until Day 43 for Arm B
Secondary outcomes:
measure: Summary of Treatment Emergent Adverse Events
timeFrame: Throughout the study
Other outcomes:
Locations:
city: Allschwil
country: Switzerland
facility: Covance Clinical Research Unit AG
state: Basel
Study officials:
affiliation: Medicines for Malaria Venture
name: Isabelle Borghini Fuhrer, PhD
role: STUDY_DIRECTOR
References: