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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
56
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.
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.
Covance Clinical Research Unit AG
Allschwil, Basel, Switzerland
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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 140 days
Non-WHO Listed Treatment Emergent Adverse Events
To assess the safety of redosing a 3-day regimen of pyronaridine-artesunate
Time frame: 140 days
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