Pharmacokinetic Study of Primaquine and Pyronaridine-Artesunate in Healthy Subjects

NCT01552330 | Completed Phase 1

• 1 other identifier: SP-C-016-11
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

The observed changes of P. falciparum sensitivity to artemisinin lead to the intensification of early detection as well as treatment monitoring in malaria infection. It is widely accepted that the development of resistance can be delayed by the use of combination therapy, especially combinations that include artemisinin derivatives (acts). As the resistance problem is considered extremely serious; as a consequence, who has recommended that all monotherapy for malaria should be stopped. Current WHO guidelines recommend that the drug combination regimens using ACT with effective partner medicines should be used to decrease the risk of development or spreading of artemisinin resistance.

Conditions

Healthy

Keywords

Primaquine; Pyronaridine-artesunate

Outcome Measures

Primary Outcomes (2)

• Area under curve for Primaquine

  Area under the concentration-time curve (AUC) for primaquine when given alone or together with Pyronaridine-Artesunate.

  42 days

• Area under cure for Pyronaridine-Artesunate

  Area under the concentration-time curve (AUC) for pyronaridine when given alone as Pyronaridine-Artesunate (PA) or together with primaquine.

  42 days

Secondary Outcomes (4)

• Area under curve for Artesunate

  42 days

• Maximum concentration and Area under curve for Primaquine and its metabolites

  42 days

• Assesment of safe and tolerability of Pyronaridine-Artesunate

  42 days

• Pharmacogenetic polymorphisms

  42 days

Study Arms (2)

Group A

EXPERIMENTAL

Primaquine only followed by Pyronaridine-Artesunate and followed by Primaquine together with Pyronaridine-Artesunate.

Drug: Primaquine and Pyronaridine-artesunate

Group B

ACTIVE COMPARATOR

Primaquine only followed by Primaquine together Pyronaridine-Artesunate and followed by Pyronaridine-Artesunate only.

Drug: Primaquine and Pyronaridine-Artesunate

Interventions

Primaquine and Pyronaridine-Artesunate DRUG

Subject will receive primaquine (PQ) then receive pyronaridine-artesunate (PA)after 1 week washout period and receive PQ together with PA for the third regimen after 8 weeks washout period Primaquine: \- Dosage: 2 tablets and Pyronaridine-Artesunate: \- Dosage: 3 tablets

Also known as: Pyramax

Group A

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
• Males and Females aged between 18 years to 60 years.
• Males and Females weighing between 45-64 kilograms.
• A female is eligible to enter and 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 abstain from sexual intercourse or agrees to using 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
• A male is eligible to enter and participate in this study if he: agrees to abstain from (or use a condom during) sexual intercourse with females of childbearing potential or lactating females; or is willing to use a condom/spermicide, during the study until completion of the follow-up procedures.
• Provide a signed and dated written informed consent prior to study participation.
• Normal electrocardiogram (ECG) with QTc \<450 msec.
• Willingness and ability to comply with the study protocol for the duration of the trial.

You may not qualify if:

• Females who are pregnant, trying to get pregnant, or are lactating.
• The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
• A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
• Subjects 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 sudden cardiac death.
• A creatinine clearance \<70 mL/min as determined by Cockcroft-Gault equation:
• CLcr (mL/min) = (140 - age) \* Wt / (72 \* Scr) (multiply answer by 0.85 for females) Where age is in years, weight (wt) is in kg, and serum creatinine (Scr) is in units of mg/dL \[Cockcroft, 1976\].
• History of alcohol or substance abuse or dependence within 6 months of the study.
• 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 half-lives (whichever is longer) prior to the first dose of study medication until the completion of the follow-up procedure, unless in the opinion of investigator, the medication will not interfere with the study procedures or compromise subject safety; the investigator will take advice from the manufacturer representative as necessary.
• The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication.
• The subject 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.
• Subjects 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.
• Subjects 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, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
• 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.
• AST or ALT \> 1 x upper limit of normal (ULN).
• Subjects with history of renal disease, hepatic disease, and/or cholecystectomy

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Hospital of Tropical Diseases, Faculty of Tropical Medicine, Mahidol University

Bangkok, 10400, Thailand

Location

Related Publications (1)

• Jittamala P, Pukrittayakamee S, Ashley EA, Nosten F, Hanboonkunupakarn B, Lee SJ, Thana P, Chairat K, Blessborn D, Panapipat S, White NJ, Day NP, Tarning J. Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects. Antimicrob Agents Chemother. 2015 Jan;59(1):505-13. doi: 10.1128/AAC.03829-14. Epub 2014 Nov 10.

  PMID: 25385096 DERIVED

MeSH Terms

Interventions

Primaquine; pyronaridine tetraphosphate, artesunate drug combination

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Podjanee Jittamala, MD

  Mahidol University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2012
• First Posted: March 13, 2012
• Study Start: May 1, 2012
• Primary Completion: October 1, 2012
• Study Completion: October 1, 2012
• Last Updated: August 28, 2013

Record last verified: 2013-08

Locations

TH (1)