Conditions: Malaria
Keywords: pyronaridine artesunate (Pyramax) artemisinin based combination therapy (ACT) metoprolol drug-drug interaction study redosing study
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: yes

Brief summary:
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:
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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Metoprolol and pyronaridine-artesunate intervention 2: pyronaridine-artesunate
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document: