Malaria
Conditions
Keywords
Mass Balance, Accelerated Mass Spectrometry (AMS), microdose, Focus of the study: ADME
Brief summary
The combination of pyronaridine and artesunate is an antimalarial therapy in development. This mass balance study is intended to determine the rate and extent of excretion of total radioactivity in urine and feces following administration of a single oral micro-dose of 14C-pyronaridine in humans.
Detailed description
This is a monocenter, open-label, non-placebo-controlled, single-group, single-dose study. Six male subjects will receive a single dose of Pyronaridine 720 mg orally administered together with 14C-Pyronaridine (approx. 100 µg, 800 nCi (29600 Bq)). Safety measurements (12-lead ECG, vital signs, blood chemistry and haematology) and adverse events will be monitored throughout the study. Subjects will come to the clinic the evening before the dosing of Pyronaridine. After the drug intake at day 1, subjects will have regular in-house periods for specimen collection up to 87 days after the drug administration. Blood, feces and urine will be collected during the hospitalisation periods. Samples will be analyzed for radioactivity by Accelerator Mass Spectrometry (AMS).
Interventions
DRUG14C-labeled Pyronaridine
Single dose of 720 mg Pyronaridine together with 14C-Pyronaridine (approx. 100 µg, 800 nCi).
Sponsors
Shin Poong Pharmaceuticals
Medicines for Malaria Venture
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
40 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male subjects between the ages of 40 and 55 years with a body weight between 60 and 90 kg and a body mass index calculated using Quetelet's Index - weight (kg)/height2 (m2) between 18.5 - 30.0 2. Signed and dated 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. All sexually active male subjects and their partners are willing to undergo contraception as follows: All male subjects, including those who are sterilised (i.e., vasectomy), should use a condom. Their female partner must also use at least 1 of the medically acceptable forms of contraceptives listed below. Male subjects must not donate sperm or have unprotected sex during the study and until 87 days after taking the dose of investigational product. Medically acceptable contraceptives for this study are: Condoms in addition to: * Intrauterine devices * Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring) * Diaphragms with spermicidal cream or gel * Cervical cap with spermicidal cream or gel * Spermicidal foam 6. 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 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 other clinical trials during the previous month in which an investigational drug or a commercially available drug was tested 15. Exposure to artificial ionizing radiation in the last 12 months (e.g., x-ray investigation, isotope studies)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 2064 hours | Radioactivity recovery in urine as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter |
| Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 2064 hours | Radioactivity recovery in feces as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Radioactivity in Blood: AUC0-t, AUC0-∞ | 42 days | Pharmacokinetic Parameters: AUC0-t: area under the plasma concentration-time curve from Hour 0 through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was collected AUC0-∞: area under the plasma concentration-time curve from Hour 0 to infinity PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose |
| Total Radioactivity in Blood: Cmax | 42 days | Pharmacokinetic Parameters: Cmax: maximum observed peak observed concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose |
| Total Radioactivity in Blood: Half-life, Tmax | 42 days | Pharmacokinetic Parameters: Half-life: computed as ln (2) / Kel Tmax: time to maximum concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pyronaridine 14C-labeled Pyronaridine: Single dose of 720 mg Pyronaridine together with 14C-Pyronaridine (approx. 100 µg, 800 nCi). | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Pyronaridine |
|---|---|
| Age, Continuous | 48.8 years STANDARD_DEVIATION 4.4 |
| BMI | 24.1 kg/m^2 STANDARD_DEVIATION 2.6 |
| Height | 180.3 cm STANDARD_DEVIATION 8.2 |
| Race/Ethnicity, Customized Caucasian | 6 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 78.0 kg STANDARD_DEVIATION 7.4 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Analysis of 14C-Pyronaridine Total Radioactivity in Feces
Radioactivity recovery in feces as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter
Time frame: 2064 hours
Population: The pharmacokinetic population consisted of all subjects without any major violations of any inclusion or exclusion criteria, who received a dose of the study drug, had not received any unauthorised drug(s) which could have adversely affected the pharmacokinetic analysis, and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 24-48h | 7.31 % administered dose | Standard Deviation 6.12 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 48-72h | 12.78 % administered dose | Standard Deviation 8.45 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 72-96h | 5.83 % administered dose | Standard Deviation 3.65 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 96-120h | 4.53 % administered dose | Standard Deviation 1.68 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 120-144h | 2.11 % administered dose | Standard Deviation 1.68 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 144-168h | 2.03 % administered dose | Standard Deviation 2.13 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 168-336h | 7.89 % administered dose | Standard Deviation 2.01 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 336-384h | 1.40 % administered dose | Standard Deviation 0.78 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 384-504h | 2.69 % administered dose | Standard Deviation 1.42 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 504-552h | 0.76 % administered dose | Standard Deviation 0.39 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 552-672h | 1.58 % administered dose | Standard Deviation 0.66 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 672-720h | 0.51 % administered dose | Standard Deviation 0.17 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 720-840h | 1.01 % administered dose | Standard Deviation 0.3 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 840-888h | 0.30 % administered dose | Standard Deviation 0.11 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 888-1008h | 0.70 % administered dose | Standard Deviation 0.31 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1008-1056h | 0.26 % administered dose | Standard Deviation 0.16 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1056-1344h | 1.23 % administered dose | Standard Deviation 0.53 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1344-1392h | 0.15 % administered dose | Standard Deviation 0.08 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1392-1680h | 0.68 % administered dose | Standard Deviation 0.13 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1680-1728h | 0.09 % administered dose | Standard Deviation 0.03 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 1728-2016h | 0.41 % administered dose | Standard Deviation 0.18 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Feces | 2016-2064h | 0.07 % administered dose | Standard Deviation 0.01 |
Primary
Analysis of 14C-Pyronaridine Total Radioactivity in Urine
Radioactivity recovery in urine as a percent of the administered dose. Continuous collection of samples was performed through 168 hours post-dose, with intermittent 48 hour collections occurring thereafter
Time frame: 2064 hours
Population: The pharmacokinetic population consisted of all subjects without any major violations of any inclusion or exclusion criteria, who received a dose of the study drug, had not received any unauthorised drug(s) which could have adversely affected the pharmacokinetic analysis, and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 504-552h | 0.84 % administered dose | Standard Deviation 0.37 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 552-672h | 1.81 % administered dose | Standard Deviation 0.69 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 0-4h | 0.09 % administered dose | Standard Deviation 0.02 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 4-8h | 0.16 % administered dose | Standard Deviation 0.08 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 8-24h | 0.60 % administered dose | Standard Deviation 0.2 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 24-48h | 0.71 % administered dose | Standard Deviation 0.08 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 48-72h | 0.67 % administered dose | Standard Deviation 0.24 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 72-96h | 0.63 % administered dose | Standard Deviation 0.1 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 96-120h | 0.55 % administered dose | Standard Deviation 0.08 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 120-144h | 0.55 % administered dose | Standard Deviation 0.09 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 144-168h | 0.60 % administered dose | Standard Deviation 0.23 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 168-336h | 3.87 % administered dose | Standard Deviation 0.69 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 336-384h | 2.38 % administered dose | Standard Deviation 0.6 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 384-504h | 2.38 % administered dose | Standard Deviation 0.6 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 672-720h | 0.61 % administered dose | Standard Deviation 0.23 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 720-840h | 1.34 % administered dose | Standard Deviation 0.58 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 840-888h | 0.46 % administered dose | Standard Deviation 0.23 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 888-1008h | 1.11 % administered dose | Standard Deviation 0.45 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1008-1056h | 0.42 % administered dose | Standard Deviation 0.14 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1056-1344h | 2.08 % administered dose | Standard Deviation 0.61 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1344-1392h | 0.27 % administered dose | Standard Deviation 0.07 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1392-1680h | 1.42 % administered dose | Standard Deviation 0.34 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1680-1728h | 0.20 % administered dose | Standard Deviation 0.04 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 1728-2016h | 1.12 % administered dose | Standard Deviation 0.26 |
| Pyronaridine | Analysis of 14C-Pyronaridine Total Radioactivity in Urine | 2016-2064h | 0.17 % administered dose | Standard Deviation 0.04 |
Secondary
Total Radioactivity in Blood: AUC0-t, AUC0-∞
Pharmacokinetic Parameters: AUC0-t: area under the plasma concentration-time curve from Hour 0 through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was collected AUC0-∞: area under the plasma concentration-time curve from Hour 0 to infinity PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose
Time frame: 42 days
Population: The pharmacokinetic population consisted of all subjects without any major violations of any inclusion or exclusion criteria, who received a dose of the study drug, had not received any unauthorised drug(s) which could have adversely affected the pharmacokinetic analysis, and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pyronaridine | Total Radioactivity in Blood: AUC0-t, AUC0-∞ | AUC0-t | 1834 day*ng-eq/ml | Standard Deviation 530 |
| Pyronaridine | Total Radioactivity in Blood: AUC0-t, AUC0-∞ | AUC0-∞ | 3731 day*ng-eq/ml | Standard Deviation 1303 |
Secondary
Total Radioactivity in Blood: Cmax
Pharmacokinetic Parameters: Cmax: maximum observed peak observed concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose
Time frame: 42 days
Population: The pharmacokinetic population consisted of all subjects without any major violations of any inclusion or exclusion criteria, who received a dose of the study drug, had not received any unauthorised drug(s) which could have adversely affected the pharmacokinetic analysis, and had evaluable pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pyronaridine | Total Radioactivity in Blood: Cmax | 271 ng-eq/ml | Standard Deviation 113 |
Secondary
Total Radioactivity in Blood: Half-life, Tmax
Pharmacokinetic Parameters: Half-life: computed as ln (2) / Kel Tmax: time to maximum concentration PK sampling performed at predose, 0.5, 1, 2, 4, 8, 12 and 24 hours, and 2, 4, 6, 7, 14, 21, 28, 35 and 42 days post-dose
Time frame: 42 days
Population: The pharmacokinetic population consisted of all subjects without any major violations of any inclusion or exclusion criteria, who received a dose of the study drug, had not received any unauthorised drug(s) which could have adversely affected the pharmacokinetic analysis, and had evaluable pharmacokinetic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pyronaridine | Total Radioactivity in Blood: Half-life, Tmax | Half-life | 33.5 days | Standard Deviation 11.4 |
| Pyronaridine | Total Radioactivity in Blood: Half-life, Tmax | Tmax | 0.111 days | Standard Deviation 0.111 |