A Randomized, Open-Label Study to Evaluate Potential Pharmacokinetic Interactions of Orally Administered Artemether-lumefantrine, Amodiaquine and Primaquine in Healthy Adult Subjects
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Area under the concentration-time curve (AUC (0-∞)
研究概览
简要总结
Primary Objective
- To characterize the potential pharmacokinetic interactions of artemether -lumefantrine, amodiaquine and primaquine in healthy adult subjects.
Secondary Objectives
- To characterize the pharmacokinetic properties of artemether-lumefantrine, amodiaquine and primaquine when given alone and in combination.
- To evaluate the safety and tolerability of co-administered artemether-lumefantrine, amodiaquine and primaquine.
- To investigate pharmacogenetic polymorphisms affecting drug levels of artemether-lumefantrine, amodiaquine and primaquine and their metabolites.
详细描述
The study design is an open-label pharmacokinetic study in healthy G6PD normal Thai subjects. This study will enroll 16 healthy subjects. Participants who pass the screening process will have 6 admissions in the hospital to receive 6 drug regimens as below
First admission visit: The subject may be randomized to receive either Artemether-Lumefantrine or Amodiaquine with more than 6 weeks washout period before second admission visit.
Second admission visit: Subject who receives Artemether-Lumefantrine from previous visit will receive amodiaquine in this visit and vice versa. This visit will required more than 6 weeks washout period before third admission visit.
Third admission visit: Every subject will receive Artemether-lumefantrine and Amodiaquine with more than 6 weeks washout period before forth admission visit.
Forth admission visit: Every subject will receive Primaquine with more than 1 week washout period before fifth admission visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
- •Male or female non-smoker aged between 18 years to 60 years.
- •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 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.
- •Normal electrocardiogram (ECG) with QTc <450 msec.
- •Willingness and ability to comply with the study protocol for the duration of the trial.
排除标准
- •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 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 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 x half-life, 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 >1.5 upper limit of normal (ULN)
- •Subjects with history of renal disease, hepatic disease, and/or cholecystectomy
- •G6PD deficient
- •Abnormal methemoglobin level (more than 3 mg/dL).
- •History of antimalarial drugs use including but not limited to mefloquine, chloroquine, primaquine, artesunate, piperaquine and pyronaridine treatment within 6 months.
- •Subject who received quinacrine in last 30 days.
研究组 & 干预措施
Group A
干预措施: Artemether-lumefantrine (Drug)
Group A
干预措施: Amodiaquine (Drug)
Group A
干预措施: Artemether-lumefantrine + Amodiaquine (Drug)
Group A
干预措施: Primaquine (Drug)
Group A
干预措施: Artemether-lumefantrine + Primaquine (Drug)
Group A
干预措施: Artemether-lumefantrine + Amodiaquine + Primaquine (Drug)
Group B
干预措施: Amodiaquine (Drug)
Group B
干预措施: Artemether-lumefantrine (Drug)
Group B
干预措施: Artemether-lumefantrine + Amodiaquine (Drug)
Group B
干预措施: Primaquine (Drug)
Group B
干预措施: Artemether-lumefantrine + Amodiaquine + Primaquine (Drug)
Group B
干预措施: Artemether-lumefantrine + Primaquine (Drug)
结局指标
主要结局
Area under the concentration-time curve (AUC (0-∞)
时间窗: 1 year
for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.
Area under the concentration-time curve AUC (0-last)
时间窗: 1 year
for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.
Maximal concentration (Cmax)
时间窗: 1 year
for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.
次要结局
- Elimination clearance (CL/F)(1 year)
- Terminal elimination half-life (t1/2)(1 year)
- Apparent volume of distribution (Vd)(1 year)
- Number of adverse events(1 year)
- Number of event concerning of abnormal electrocardiographic(1 year)
- Number of event concerning of abnormal vital signs(1 year)
- Number of event concerning of abnormal laboratory values(1 year)
- Identify polymorphisms of cytochrome 450(1 year)