Malaria
Conditions
Keywords
malaria, artemisinin-based combination therapy (ACT), antimalarial, pyronaridine artesunate (Pyramax)
Brief summary
The primary objective of the study is to determine any drug interaction between the antimalarial Pyramax (pyronaridine artesunate) and the protease inhibitor ritonavir in healthy subjects. The secondary objective of the study is to assess further the safety of Pyramax in this setting.
Detailed description
This is a phase I, open label, randomized study to determine any drug interaction between Pyramax (pyronaridine/artesunate) and the protease inhibitor ritonavir in healthy volunteers. A total of 34 healthy volunteers (17 per treatment arm) will be enrolled in the study so that at least 30 (15 per treatment arm) will complete it. Subjects will be randomly assigned in a 1:1 ratio to receive either ritonavir (100 mg) twice daily for 17 days from Day 1-17 plus Pyramax (180:60 mg) once daily for 3 days from Day 8-10 in Arm A or pyronaridine/artesunate (180:60 mg) alone once daily for 3 days from Day 1-3 in Arm B. Subjects will come to the clinic the evening before first dosing of Pyramax / ritonavir. If enrolled, and according to the treatment arm, subjects will stay in the clinic and attend subsequent visits as follows: Arm A: * Inpatient day -1 (evening) to day 17 * Ambulatory clinic visit once daily (morning) on day 22, 29, 36, 43 and 50 (end of study visit) Arm B: * Inpatient day -1 (evening) to day 4 (morning), * Ambulatory clinic visit once daily (morning) on Day 5, 6, 8, 15, 22, 29, 36, and 43.(end of study visit) The subjects will be evaluated for pharmacokinetic parameters and safety/tolerability.
Interventions
DRUGRitonavir and Pyramax
100 mg ritonavir (one soft gelatin capsule twice per day over 17 days, the evening capsule on day 1 will be omitted) and Pyramax (pyronaridine/artesunate) 180:60 mg (3 to 4 tablets once per day according to weight for 3 days).
DRUGPyramax
Pyramax (pyronaridine/artesunate) 180:60 mg (3 to 4 tablets once per day according to weight for 3 days).
Sponsors
Shin Poong Pharmaceuticals
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female subjects between the ages of 18 and 55 years with a body weight between 50 and 90 kg and a body mass index calculated using Quetelet's Index - weight (kg)/height (m2) between 18.5-30.0 2. Signed and dated a 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. 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) 6. Female subjects of childbearing potential with a negative urine pregnancy test at screening and a negative plasma pregnancy test prior to inclusion and who agreed to one of the following methods: * Double barrier method of contraception for 2 weeks before first study drug administration and throughout the entire study follow up period * Partner(s) who had undergone vasectomy and has been negative for sperm for at least 6 months 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 clinical abnormality 2. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine or artesunate or other artemisinins or ritonavir 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 any clinical study in last 2 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics Analysis: Half-life, Tmax | Until Day 50 for Arm A and until Day 43 for Arm B | Half-life and Tmax for pyronaridine, artesunate, DHA: Tmax - time of the maximum observed concentration Half life - apparent plasma terminal elimination half-life, computed as ln (2)/Kel Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose. |
| Pharmacokinetics Analysis: Cmax | Until Day 50 for Arm A and until Day 43 for Arm B | Cmax for pyronaridine, artesunate, DHA: Cmax - maximum peak observed concentration Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose. |
| Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Until Day 50 for Arm A and until Day 43 for Arm B | AUC0-tau, AUC0-∞ for pyronaridine, artesunate, DHA: AUC0-tau - area under the concentration-time curve from Hour 0 to the scheduled time of the next dose AUC0-∞ - area under the concentration-time curve from Hour 0 through the last quantifiable concentration time Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Treatment Emergent Adverse Events | Throughout the study | Including all the treatment emergent adverse events, the number of subjects discontinued due to adverse events and the number of subjects with serious adverse events. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Ritonavir Plus Pyramax 7 days of ritonavir followed by 3 days of ritonavir plus Pyramax followed by 7 days of ritonavir | 17 |
| Arm B Pyramax 3 day treatment course of Pyramax | 17 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Elevated liver enzymes | 4 | 0 |
| Overall Study | Vomiting | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A Ritonavir Plus Pyramax | Arm B Pyramax | Total |
|---|---|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 10.6 | 43.7 years STANDARD_DEVIATION 10 | 43.0 years STANDARD_DEVIATION 10.3 |
| BMI | 23.1 kg/m^2 STANDARD_DEVIATION 2.2 | 24.2 kg/m^2 STANDARD_DEVIATION 2.6 | 23.65 kg/m^2 STANDARD_DEVIATION 2.4 |
| Race/Ethnicity, Customized Caucasian | 17 Participants | 17 Participants | 34 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 |
| other Total, other adverse events | 10 / 17 | 13 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 |
Outcome results
Primary
Pharmacokinetics Analysis: AUC0-tau, AUC0-∞
AUC0-tau, AUC0-∞ for pyronaridine, artesunate, DHA: AUC0-tau - area under the concentration-time curve from Hour 0 to the scheduled time of the next dose AUC0-∞ - area under the concentration-time curve from Hour 0 through the last quantifiable concentration time Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.
Time frame: Until Day 50 for Arm A and until Day 43 for Arm B
Population: Number of subjects studied
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Pyronaridine AUC0-tau (adjusted to a common dose of 9.72 mg/kg) | 229 hours*ng/ml | Standard Deviation 82 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Pyronaridine AUC0-∞ (adjusted to a common dose of 9.72 mg/kg) | 1244 hours*ng/ml | Standard Deviation 292 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Artesunate AUC0-tau (adjusted to common dose of 3.25 mg/kg) | 185.4 hours*ng/ml | Standard Deviation 105.6 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Artesunate AUC0-∞(adjusted to common dose of 3.25 mg/kg) | 185.4 hours*ng/ml | Standard Deviation 105.6 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | DHA AUC0-tau (adjusted for common 3.25 mg/kg artesunate dose) | 1308 hours*ng/ml | Standard Deviation 544 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | DHA AUC0-∞ (adjusted for common 3.25 mg/kg artesunate dose) | 1310 hours*ng/ml | Standard Deviation 545 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | DHA AUC0-tau (adjusted for common 3.25 mg/kg artesunate dose) | 1978 hours*ng/ml | Standard Deviation 622 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Pyronaridine AUC0-tau (adjusted to a common dose of 9.72 mg/kg) | 222 hours*ng/ml | Standard Deviation 80 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Artesunate AUC0-∞(adjusted to common dose of 3.25 mg/kg) | 149 hours*ng/ml | Standard Deviation 60 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Pyronaridine AUC0-∞ (adjusted to a common dose of 9.72 mg/kg) | 1318 hours*ng/ml | Standard Deviation 481 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | DHA AUC0-∞ (adjusted for common 3.25 mg/kg artesunate dose) | 1982 hours*ng/ml | Standard Deviation 628 |
| Arm B Pyramax | Pharmacokinetics Analysis: AUC0-tau, AUC0-∞ | Artesunate AUC0-tau (adjusted to common dose of 3.25 mg/kg) | 150 hours*ng/ml | Standard Deviation 60 |
Primary
Pharmacokinetics Analysis: Cmax
Cmax for pyronaridine, artesunate, DHA: Cmax - maximum peak observed concentration Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.
Time frame: Until Day 50 for Arm A and until Day 43 for Arm B
Population: Number of subjects studied
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Cmax | Pyronaridine Cmax (adjusted to a common dose of 9.72 mg/kg) | 480.2 ng/ml | Standard Deviation 145.1 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Cmax | Artesunate Cmax (adjusted to common dose of 3.25 mg/kg) | 128.2 ng/ml | Standard Deviation 91.2 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Cmax | DHA Cmax (adjusted for common 3.25 mg/kg artesunate dose) | 611.4 ng/ml | Standard Deviation 273.4 |
| Arm B Pyramax | Pharmacokinetics Analysis: Cmax | Pyronaridine Cmax (adjusted to a common dose of 9.72 mg/kg) | 407.5 ng/ml | Standard Deviation 167.1 |
| Arm B Pyramax | Pharmacokinetics Analysis: Cmax | Artesunate Cmax (adjusted to common dose of 3.25 mg/kg) | 108.7 ng/ml | Standard Deviation 49.1 |
| Arm B Pyramax | Pharmacokinetics Analysis: Cmax | DHA Cmax (adjusted for common 3.25 mg/kg artesunate dose) | 779.2 ng/ml | Standard Deviation 267.5 |
Primary
Pharmacokinetics Analysis: Half-life, Tmax
Half-life and Tmax for pyronaridine, artesunate, DHA: Tmax - time of the maximum observed concentration Half life - apparent plasma terminal elimination half-life, computed as ln (2)/Kel Blood samples for pyronaridine analysis were taken at Day 8 predose, Day 9 predose, Day 10 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose, and Days 11,12, 13, 15, 22, 29, 36 and 43. Blood samples for artesunate / DHA analysis were taken at Day 10 predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours postdose.
Time frame: Until Day 50 for Arm A and until Day 43 for Arm B
Population: Number of subjects studied
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Pyronaridine half- life (adjusted to a common dose of 9.72 mg/kg) | 384 hours | Standard Deviation 223.2 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Pyronaridine Tmax (adjusted to a common dose of 9.72 mg/kg) | 2.32 hours | Standard Deviation 2.16 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Artesunate half-life (adjusted to common dose of 3.25 mg/kg) | 0.425 hours | Standard Deviation 0.131 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Artesunate Tmax (adjusted to common dose of 3.25 mg/kg) | 1.22 hours | Standard Deviation 0.69 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | DHA half-life (adjusted for common 3.25 mg/kg artesunate dose) | 2.27 hours | Standard Deviation 1.04 |
| Arm A Ritonavir Plus Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | DHA Tmax (adjusted for common 3.25 mg/kg artesunate dose) | 1.90 hours | Standard Deviation 0.71 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | DHA half-life (adjusted for common 3.25 mg/kg artesunate dose) | 2.35 hours | Standard Deviation 0.9 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Pyronaridine half- life (adjusted to a common dose of 9.72 mg/kg) | 321.6 hours | Standard Deviation 69.6 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Artesunate Tmax (adjusted to common dose of 3.25 mg/kg) | 0.84 hours | Standard Deviation 0.43 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Pyronaridine Tmax (adjusted to a common dose of 9.72 mg/kg) | 1.44 hours | Standard Deviation 0.36 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | DHA Tmax (adjusted for common 3.25 mg/kg artesunate dose) | 1.44 hours | Standard Deviation 0.403 |
| Arm B Pyramax | Pharmacokinetics Analysis: Half-life, Tmax | Artesunate half-life (adjusted to common dose of 3.25 mg/kg) | 0.465 hours | Standard Deviation 0.197 |
Secondary
Summary of Treatment Emergent Adverse Events
Including all the treatment emergent adverse events, the number of subjects discontinued due to adverse events and the number of subjects with serious adverse events.
Time frame: Throughout the study
Population: Number of subjects studied
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A Ritonavir Plus Pyramax | Summary of Treatment Emergent Adverse Events | Mild treatment emergent adverse events | 12 Participants |
| Arm A Ritonavir Plus Pyramax | Summary of Treatment Emergent Adverse Events | Severe treatment emergent adverse events | 0 Participants |
| Arm A Ritonavir Plus Pyramax | Summary of Treatment Emergent Adverse Events | Subjects with serious adverse events | 0 Participants |
| Arm A Ritonavir Plus Pyramax | Summary of Treatment Emergent Adverse Events | Subjects discontinued due to adverse events | 4 Participants |
| Arm A Ritonavir Plus Pyramax | Summary of Treatment Emergent Adverse Events | Moderate treatment emergent adverse events | 6 Participants |
| Arm B Pyramax | Summary of Treatment Emergent Adverse Events | Subjects with serious adverse events | 0 Participants |
| Arm B Pyramax | Summary of Treatment Emergent Adverse Events | Mild treatment emergent adverse events | 15 Participants |
| Arm B Pyramax | Summary of Treatment Emergent Adverse Events | Moderate treatment emergent adverse events | 3 Participants |
| Arm B Pyramax | Summary of Treatment Emergent Adverse Events | Severe treatment emergent adverse events | 0 Participants |
| Arm B Pyramax | Summary of Treatment Emergent Adverse Events | Subjects discontinued due to adverse events | 1 Participants |