Malaria
Conditions
Keywords
Pyronaridine artesunate tablet, Pyronaridine artesunate granules, Pyramax tablet, Pyramax granules, Bioavailability, artemisinin based combination therapy (ACT)
Brief summary
The primary objective of this study is to compare the bioavailability of two formulations (tablets and granules for dispersion) of the antimalarial drug pyronaridine-artesunate \[3:1\] (Pyramax, PA) in healthy adults. The secondary objective is to compare the safety of the two PA formulations and liver function test changes following the first and second administrations.
Detailed description
This is a Phase I, single centre, open-label, randomised, two-way cross-over study in healthy volunteers to compare the bioavailability of two formulations of pyronaridine-artesunate, in tablet and in granule formulation. The study population will include 60 healthy volunteers, comprising male and female adults aged 20 to 45 years inclusive. The volunteers will be randomised equally on Day -1 to one of two sequences: Sequence 1 (tablets in Period 1, granules in Period 2), or Sequence 2 (granules in Period 1, tablets in Period 2). The periods will be separated by a 60-day wash-out period. Each of the two pyronaridine-artesunate formulations will be administered as a single dose of either 180:60 mg pyronaridine-artesunate tablets (3 tablets) or 60:20 mg pyronaridine-artesunate granules (9 sachets). The total dose of each formulation administered is 540:180 mg pyronaridine-artesunate. The study duration from the first study drug administration (Day 1) through to the last follow-up will be approximately 103 days. Screening is to be performed within 28 days before Day 1. Adverse events will be monitored throughout the study (and to resolution if necessary) to assess the general safety and tolerability of the treatments.
Interventions
DRUGPyronaridine-artesunate granules
DRUGPyronaridine-artesunate tablets
Sponsors
Shin Poong Pharmaceutical Co. Ltd.
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female subjects between the ages of 20 and 45 years, inclusive. (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests) * Weight between 50 kg and 80 kg and Body Mass Index (BMI) calculated using Quetelet's Index - weight(kg)/height (m2) between 18.5 to 27 kg/m2; * An informed consent document signed and dated by the subject (prior to screening and any study activities, including discontinuation of any prohibited medications) * Strictly normal values of alanine aminotransferase(ALT), aspartate aminotransferase (AST), and bilirubin, and normal or abnormal but clinically insignificant results of the other blood and urine laboratory parameters at screening. * Female subjects of non-childbearing potential \[i.e., physiologically incapable of becoming pregnant, including any female who was post-menopausal (i.e., one year without menses) or who has undergone sterilization (via hysterectomy or bilateral tubal ligation)\] * Female subjects of childbearing potential with a negative urine pregnancy test at screening, and a negative pregnancy blood test on admission, and who : * agree to double barrier method of contraception for 4 weeks before first study drug administration and throughout the entire study follow up period, or * whose partner has undergone vasectomy and has been negative for sperm for at least 6 months * Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion criteria
* Known history or evidence of clinically significant disorders such as cardiovascular (including arrhythmia, acute corrected QT interval (QTc) greater or equal to 450 milliseconds), 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) * Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins * Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab) * Seropositive HIV antibody, seropositive syphilis \[Syphilis reagin test (+)\] * Previous exposure to pyronaridine-artesunate (Pyramax) * Present or recent history (last two years) of tobacco abuse (≥10 cigarettes/day) * Known or suspected alcohol abuse or illicit drug use up to 5 years before the study start or positive findings on urine drug screen * Intake of alcoholic beverages or caffeine-containing food or beverages, such as coffee, tea, chocolate, or cola, 48 hours before study drug administration * Intake of grapefruit, Seville oranges or products containing these from 72 hours before the start of study drug administration * Gilbert's disease * Use of over-the-counter (OTC) medications, including vitamins, analgesics, antipyretics or antacids within 7 days before study drug administration * Use of prescription medications within 14 days before the start of study drug administration or required chronic use of any prescription medication * Use of enzyme-altering agents (e.g. barbiturates, phenothiazines, cimetidine, etc.) within 30 days before the start of study drug administration * Plasma donation within 60 days before the start of study drug administration * Blood donation of 500 mL or more within 60 days before the start of study drug administration * Participation AND having had drug administration in any other clinical study within the 60 days before start of study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA) | First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103) | Pharmacokinetic blood sampling for first or second intervention dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103) | Pharmacokinetic blood sampling for first or second intervention dose |
| Safety Evaluation - Summary of Adverse Events | End of study (Day 103) | — |
Countries
South Korea
Participant flow
Pre-assignment details
30 Volunteers were recruited to Sequence 1 and 30 to Sequence 2 (60 total). Since this is a crossover study from tablets to granules (Sequence 1) or vice versa (Sequence 2), overall there is a planned 60 volunteers taking tablets and 60 volunteers taking granules.
Participants by arm
| Arm | Count |
|---|---|
| All Volunteers Enrolled Includes both tablets and granules groups | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Lost to Follow-up | 2 | 3 |
| First Intervention | Meeting the non-redosing criteria | 0 | 1 |
| First Intervention | Withdrawal by Subject | 5 | 1 |
| Second Intervention | Adverse Event | 3 | 3 |
Baseline characteristics
| Characteristic | All Volunteers Enrolled |
|---|---|
| Age, Customized 20-24 years | 33 Participants |
| Age, Customized 25-29 years | 18 Participants |
| Age, Customized 30-39 years | 8 Participants |
| Age, Customized 40-45 years | 1 Participants |
| BMI | 22.78 kg/m^2 STANDARD_DEVIATION 1.6 |
| Race/Ethnicity, Customized Korean | 60 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 53 |
| other Total, other adverse events | 22 / 55 | 23 / 53 |
| serious Total, serious adverse events | 0 / 55 | 0 / 53 |
Outcome results
Primary
Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA)
Pharmacokinetic blood sampling for first or second intervention dose
Time frame: First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)
Population: Number analyzed includes only subjects completing both periods with estimable parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total Receiving Pyronaridine-artesunate Tablets | Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA) | AUC 0-t pyronaridine | 11640 ng*h/ml | Standard Deviation 4344 |
| Total Receiving Pyronaridine-artesunate Tablets | Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA) | AUC 0-t DHA | 1119 ng*h/ml | Standard Deviation 364 |
| Total Receiving Pyronaridine-artesunate Granules | Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA) | AUC 0-t pyronaridine | 11324 ng*h/ml | Standard Deviation 3927 |
| Total Receiving Pyronaridine-artesunate Granules | Area Under the Concentration-time Curve From Hour 0 to the Last Sampling Point (AUC 0-t) for Pyronaridine and Dihydroartemisinin (DHA) | AUC 0-t DHA | 829 ng*h/ml | Standard Deviation 328 |
Secondary
Safety Evaluation - Summary of Adverse Events
Time frame: End of study (Day 103)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Adverse event before treatment | 2 Participants |
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Treatment-emergent adverse event | 22 Participants |
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Treatment-related adverse event | 14 Participants |
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Serious adverse event | 0 Participants |
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Serious adverse drug reaction | 0 Participants |
| Total Receiving Pyronaridine-artesunate Tablets | Safety Evaluation - Summary of Adverse Events | Adverse event leading to discontinuation | 3 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Serious adverse drug reaction | 0 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Adverse event before treatment | 0 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Serious adverse event | 0 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Treatment-emergent adverse event | 23 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Adverse event leading to discontinuation | 3 Participants |
| Total Receiving Pyronaridine-artesunate Granules | Safety Evaluation - Summary of Adverse Events | Treatment-related adverse event | 14 Participants |
Secondary
Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA
Pharmacokinetic blood sampling for first or second intervention dose
Time frame: First intervention: Day 1 pre-dose to Day 43 visit (D1, 2, 3, 4, 6, 8, 15, 22, 29, 36, 43) ; second intervention: Day 61 pre-dose to Day 103 visit (D61, 62, 63, 64, 66, 68, 75, 82, 89, 96, 103)
Population: Number analyzed includes only subjects completing both periods with estimable parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax artesunate | 0.98 hours | Standard Deviation 0.544 |
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax DHA | 1.46 hours | Standard Deviation 0.69 |
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life artesunate | 0.33 hours | Standard Deviation 0.0852 |
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life pyronaridine | 639 hours | Standard Deviation 262.2 |
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life DHA | 1.50 hours | Standard Deviation 0.713 |
| Total Receiving Pyronaridine-artesunate Tablets | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax pyronaridine | 2.1 hours | Standard Deviation 2 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life DHA | 1.43 hours | Standard Deviation 0.718 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax pyronaridine | 1.7 hours | Standard Deviation 1.6 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life pyronaridine | 591.8 hours | Standard Deviation 372.9 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax artesunate | 1.52 hours | Standard Deviation 0.921 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Tmax DHA | 2.26 hours | Standard Deviation 0.871 |
| Total Receiving Pyronaridine-artesunate Granules | Tmax and Terminal Half Life for Pyronaridine, Artesunate and DHA | Half-life artesunate | 0.71 hours | Standard Deviation 0.112 |