This is an open-label pharmacokinetic study in 24 healthy Thai participants. Participants will be admitted in the inpatient ward and each participant will attend a total of 4 visits, including one screening visit and three hospital admissions. Participants will be randomized into one of six groups.

Each group will receive 3 drug regimens consisting of (1) piperaquine, (2) pyronaridine plus artesunate, or (3) piperaquine, pyronaridine, and artesunate, administered once per day for three consecutive days in different sequential orders.

After each regimen, participants will be followed up for six weeks for clinical assessments and laboratory evaluations to study the pharmacokinetics. A washout period of at least eight weeks will be implemented between each regimen.

This study is funded by the Global Health Innovative Technology Fund (GHIT Fund), Tokyo, Japan, under grant number G2025-117.

This study will enroll 24 healthy Thai participants. Participants will complete one screening visit and three inpatient study periods.

Participants will be randomly assigned to one of six study groups and will receive three different study drugs in a crossover design, as described below:

• Study drug 1: Piperaquine
• Study drug 2: Pyronaridine and artesunate
• Study drug 3: Piperaquine, pyronaridine and artesunate

Each treatment study drug will be administered for three consecutive days. The order of administration will differ by study group as follows:

Group 1 (n = 4): Study drug 1 → Study drug 2 → Study drug 3

Group 2 (n = 4): Study drug 1 → Study drug 3 → Study drug 2

Group 3 (n = 4): Study drug 2 → Study drug 1 → Study drug 3

Group 4 (n = 4): Study drug 2 → Study drug 3 → Study drug 1

Group 5 (n = 4): Study drug 3 → Study drug 1 → Study drug 2

Group 6 (n = 4): Study drug 3 → Study drug 2 → Study drug 1

After each treatment period, participants will be followed for six weeks, during which seven follow-up visits will be conducted for clinical assessments and blood sampling. A washout period of at least eight weeks will be observed between treatment periods to allow for complete elimination of the study drugs from the body.

Each participant will take part in the study for about 6 months. The entire study is expected to last about 12 months.

Inclusion Criteria:

1. Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.

2. Male or female non-smoker aged between 18 years to 60 years, weighting between 45 and 85 kg.

3. A female is eligible to participate in this study if she is:

   • of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy
   • or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy
   • or of childbearing potential, has a negative serum pregnancy test at screening and prior to start the study drug in each period, and agrees to abstain from sexual intercourse or use effective contraceptive methods (e.g., intrauterine device, hormonal contraceptive drug, tubal ligation or female barrier method with spermicide) during the study until completion of the follow-up procedures

4. Normal electrocardiogram (ECG) with QTc <450 msec.

5. Willingness and ability to comply with the study protocol for the duration of the trial.

6. Participants is willing and able to give written informed consent for participation in the study

Exclusion Criteria:

1. Females who are pregnant, trying to get pregnant, or are lactating.
2. The participant has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
3. A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
4. Participants with a personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes (heart failure, hypokalemia) or with a family history of long QT syndrome, Brugada syndrome, or sudden cardiac death.
5. Abnormal serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) <70 mL/min as determined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
6. History of alcohol or substance abuse or dependence within 6 months of the study.
7. Use of prescription or non-prescription drugs except paracetamol at doses of up to 2 grams/day, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 times the drug half-life (whichever is longer) prior to the first dose of study medication until the completion of the follow-up procedure, unless in the opinion of the investigator, the medication will not interfere with the study procedures or compromise participant safety; the investigator will take advice from the manufacturer representative as necessary.
8. The participant has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 times the drug half-life, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication.
9. The participant is unwilling to abstain from ingesting alcohol within 48 hours prior to the first dose of study medication until collection of the final pharmacokinetic sample during each regimen.
10. Participants who have donated blood to the extent that participation in the study would result in more than 300 mL blood donated within a 30-day period. Note: This does not include plasma donation.
11. Participants who have a history of allergy to the study drug or drugs of this class, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the trial. In addition, if heparin is used during pharmacokinetic sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
12. Lack of suitability for participation in this study, including but not limited to, unstable medical conditions, systemic disease manifested by tendency to granulocytopenia e.g. rheumatoid arthritis and lupus erythematosus that in the opinion of the investigator would compromise their participation in the trial.
13. AST or ALT >1.5 times the upper limit of normal (ULN)
14. History of antimalarial drugs use including but not limited to mefloquine, chloroquine, primaquine, artesunate, piperaquine and pyronaridine treatment within 6 months.

With participant's consent, participant's clinical data and results from blood analyses stored in our database may be shared with other researchers to use in the future in accordance with the current Data Sharing Policy. However, the other researchers will not be given any information that could identify the participant.