Pyronaridine Artesunate-Ritonavir Drug-drug Interaction Study

Malaria Clinical Trial

Official title:

Open-label, Randomised, Drug Interaction Study of Pyramax (Pyronaridine Artesunate) and the Protease Inhibitor Ritonavir in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01156389
• Other study ID #: SP-C-010-10
• Status: Completed
• Phase: Phase 1
• Start date: July 2010
• Est. completion date: September 2010

Study information

• Verified date: February 2023
• Source: Medicines for Malaria Venture
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: September 2010
• Est. primary completion date: August 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Malaria

Intervention

Drug:
• Ritonavir and Pyramax
100 mg ritonavir (one soft gelatin capsule twice per day over 17 days, the evening capsule on day 1 will be omitted) and Pyramax (pyronaridine/artesunate) 180:60 mg (3 to 4 tablets once per day according to weight for 3 days).
• Pyramax
Pyramax (pyronaridine/artesunate) 180:60 mg (3 to 4 tablets once per day according to weight for 3 days).

Locations

Country	Name	City	State
Switzerland	Covance Clinical Research Unit AG	Allschwil	Basel

Sponsors (2)

Lead Sponsor	Collaborator
Medicines for Malaria Venture	Shin Poong Pharmaceuticals

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics Analysis: Half-life, Tmax	Half-life and Tmax for pyronaridine, artesunate, DHA: Tmax - time of the maximum observed concentration Half life - apparent plasma terminal elimination half-life, computed as ln (2)/Kel; Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43.; Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.	Until Day 50 for Arm A and until Day 43 for Arm B
Primary	Pharmacokinetics Analysis: Cmax	Cmax for pyronaridine, artesunate, DHA: Cmax - maximum peak observed concentration; Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43.; Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.	Until Day 50 for Arm A and until Day 43 for Arm B
Primary	Pharmacokinetics Analysis: AUC0-tau, AUC0-8	AUC0-tau, AUC0-8 for pyronaridine, artesunate, DHA: AUC0-tau - area under the concentration-time curve from Hour 0 to the scheduled time of the next dose AUC0-8 - area under the concentration-time curve from Hour 0 through the last quantifiable concentration time; Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43.; Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.	Until Day 50 for Arm A and until Day 43 for Arm B
Secondary	Summary of Treatment Emergent Adverse Events	Including all the treatment emergent adverse events, the number of subjects discontinued due to adverse events and the number of subjects with serious adverse events.	Throughout the study