Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet

Phase I, Randomized, Single Dose, Bioequivalence Trial of Pyronaridine Artesunate To-be-marketed Tablet to the Clinical Trial Reference Tablet

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00682630

Enrollment

Registered

2008-05-22

Start date

2007-09-30

Completion date

2008-09-30

Last updated

2023-02-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Malaria

Keywords

Malaria, anti-malarial, pyronaridine, pyronaridine artesunate (Pyramax), artemisinin based combination therapy (ACT)

Brief summary

The primary objective of this study is to determine the bioequivalence of the combination of pyronaridine and artesunate (180:60mg) to-be-marketed tablet to the clinical trial reference tablet administered as a single total dose of 720:240 mg in healthy adults. The secondary objective is to assess the safety of the two formulations.

Detailed description

This is a phase I, randomized, single dose, two-way cross-over study of two tablet formulations of the combination of pyronaridine and artesunate (180:60 mg). The study will include 42 healthy participants, comprising male and female adults. Participants will be randomized to receive either reference tablet formulation or to-be-marketed formulation first and then will be crossed over to receive the opposite Intervention. The study will consist of two single dose treatments of 720:240 mg tablets, separated by a washout period of 43 days. Participants will go to the clinic the evening before dosing (dosing days were Day 0 for period 1 and Day 43 for period 2) under fasting condition and remain in the hospital for 24 hours after receiving dosing. Participants will stay in the hospital for 24 hours after their arrival at the clinic. They will return to the clinic at Day 2, 3, 5, 7, 14, 21, 28, 35 and 42 on an ambulatory basis. At Day 43, the dosing for the second sequence will start and a similar schedule of visits will be followed. Each participant will be followed-up for an additional 42 days after the start of the second study period, until the final visit (Day 85). The total duration of participation is 85 days plus a maximum of 2 weeks screening period.

Interventions

DRUGpyronaridine artesunate clinical trial reference tablets

Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)

DRUGpyronaridine artesunate to-be-marketed tablets

Single total oral dose of 720:240 mg (4 tablets of 180:60 mg)

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 45 Years

Healthy volunteers

Yes

Inclusion criteria

1. Male or female subjects between the ages of 18 and 45 years with a body weight between 55 and 75 kg and a body mass index using Quetelet's Index - weight (kg)/height2 (m2) between 18-28 2. Signed and dated written informed consent form 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 clinical investigator 4. Normal (or abnormal and clinically insignificant) laboratory values 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) 6. Female subjects of childbearing potential with a negative urine pregnancy test at screening and who agreed to one of the accepted forms of contraception 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 3. Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab) 4. Known seropositive HIV antibody 5. Previous participation in any clinical trial with pyronaridine artesunate 6. Presence or recent history (last two years) of tobacco abuse (≥10 cigarettes/day) 7. Known or suspected alcohol abuse or illicit drug use 10 years before the study start or positive findings on urine drug screen 8. Intake of alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 24 h before study drug administration 9. Use of over-the-counter (OTC) medications, including vitamins, analgesics, or antacids, 72 h 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.) 30 days before the study start 12. Plasma donation 3 months before the study start 13. Blood donation of 500 mL or more 3 months before the study start 14. Participation in an investigational drug study 3 months before randomization

Design outcomes

Primary

Measure	Time frame	Description
Pyronaridine Pharmacokinetics: Tmax, Half-life	Sampling performed at predose at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period	Tmax: time to maximum concentration Half-life: computed as ln (2)/kel
Pyronaridine (PP), Artesunate (AS), Dihydroartemisinin (DHA) Pharmacokinetics: Cmax	PP sampling performed at predose at at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period AS, DHA sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period	Cmax: maximum peak observed concentration
Artesunate (AS) and Dihydroartemisinin (DHA) Pharmacokinetics: Tmax, Half-life	Sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period	Tmax: time to maximum concentration Half-life: computed as ln (2)/kel
Pyronaridine Pharmacokinetics: AUC0-last, AUC0-∞	Sampling performed at predose at 0 h and at, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12, 24, 48, 72 h and on Day 5, 7, 14, 21, 28, 35, 42 for each period	AUC0-last: Area under the concentration-time curve from time 0 (0 h) through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn AUC0-∞: Area under the concentration-time curve from time 0 (0 h) to infinity, computed using the linear trapezoidal rule as AUClast + CLQCT / Kel
Artesunate (AS) and Dihydroartemisinin (DHA): AUC0-last, AUC0-∞	Sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period	AUC0-last: Area under the concentration-time curve from time 0 (0 h) through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn AUC0-∞: Area under the concentration-time curve from time 0 (0 h) to infinity, computed using the linear trapezoidal rule as AUClast + CLQCT / Kel

Countries

Switzerland

Participant flow

Participants by arm

Arm	Count
Clinical Trial Reference Tablets First, Then To-Be-Marketed Tablets Participants first received clinical trial reference 720:240 mg tablets on Day 0. After a washout period of 43 days, they then received to-be-marketed 720:240 mg tablets on Day 43, with a follow-up period of 42 days.	21
To-Be-Marketed Tablets First, Then Clinical Trial Reference Tablets Participants first received to-be-marketed 720:240 mg tablets on Day 0. After a washout period of 43 days, they then received clinical trial reference 720:240 mg tablets on Day 43, with a follow-up period of 42 days.	21
Total	42

Baseline characteristics

Characteristic	Clinical Trial Reference Tablets First, Then To-Be-Marketed Tablets	To-Be-Marketed Tablets First, Then Clinical Trial Reference Tablets	Total
Age, Continuous	34 years STANDARD_DEVIATION 7.8	33.5 years STANDARD_DEVIATION 4.9	33.8 years STANDARD_DEVIATION 7.1
BMI	23.5 kg/m^2 STANDARD_DEVIATION 1.4	23.3 kg/m^2 STANDARD_DEVIATION 3	23.4 kg/m^2 STANDARD_DEVIATION 2
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	7 Participants	15 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants	14 Participants	27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants	7 Participants	15 Participants
Race (NIH/OMB) White	13 Participants	14 Participants	27 Participants
Sex: Female, Male Female	7 Participants	11 Participants	18 Participants
Sex: Female, Male Male	14 Participants	10 Participants	24 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 39	0 / 40
other Total, other adverse events	26 / 39	28 / 40
serious Total, serious adverse events	0 / 39	0 / 40

Outcome results

Primary

Artesunate (AS) and Dihydroartemisinin (DHA): AUC0-last, AUC0-∞

AUC0-last: Area under the concentration-time curve from time 0 (0 h) through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was drawn AUC0-∞: Area under the concentration-time curve from time 0 (0 h) to infinity, computed using the linear trapezoidal rule as AUClast + CLQCT / Kel

Time frame: Sampling performed at predose at 0 h and at 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 8, 12 h for each period