A Phase 1, Open-Label, 4-Part, Fixed-Sequence Study to Assess the Effect of Itraconazole, a Strong CYP3A Inhibitor, the Effect of Fluconazole, a Moderate CYP3A/2C9 Inhibitor, the Effect of Rifampin, a Strong CYP3A Inducer, and the Effect of Rabeprazole, a Proton Pump Inhibitor on the Pharmacokinetics of HMPL-689 in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Hutchmed
- 入组人数
- 59
- 试验地点
- 1
- 主要终点
- Cmax
研究概览
简要总结
An open-label study to determine effect of Itraconazole, Fluconazole, Rifampin, and Rabeprazole on the PK of HMPL-689
详细描述
A phase 1, open-label, 4-part, 2-period, fixed-sequence study to assess the effect of Itraconazole, a strong CYP3A inhibitor, the effect of Fluconazole, a moderate CYP3A/2C9 inhibitor, the effect of Rifampin, a strong CYP3A inducer, and the effect of Rabeprazole, a proton pump inhibitor on the pharmacokinetics (PK) of a single oral dose of HMPL-689 in study participants. The secondary objective is to evaluate the safety of a single oral dose of HMPL-689 administered with and without Itraconazole, Fluconazole, Rifampin, or Rabeprazole in study participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female between the ages of 18 and 55 years old (inclusive) at the time of informed consent.
- •Body mass index (BMI) >18 and ≤29.9 kg/m2 at screening.
- •Females must be postmenopausal (defined as absence of menses for at least 1 year without alternative medical cause) or permanently sterile by total hysterectomy, bilateral oophorectomy, or bilateral salphingectomy.
- •Males, including those who have had a successful vasectomy, must use a condom during sexual intercourse with women of childbearing potential starting from their first dose of study drug through 30 days after their last dose of study drug. Alternatively, abstinence is allowed if it is the normal and preferred lifestyle of the healthy volunteer.
- •Must provide written informed consent prior to any study-specific screening procedures.
- •Willing and able to comply with all aspects of the protocol, as determined by the PI.
排除标准
- •Known history of any gastrointestinal surgery or any condition possibly affecting drug absorption (eg, cholecystectomy, gastrectomy, achlorhydria, peptic ulcer disease, history of stomach or intestinal surgery, or resection). Appendectomy and hernia repair are allowed.
- •Clinically significant illness within 8 weeks or a clinically significant infection within 4 weeks prior to the first dose.
- •Evidence of a clinically significant deviation from normal in the physical examination, vital signs, or clinical laboratory determinations at screening or at Day -1 Check-in (baseline).
- •Systolic blood of pressure >140 mmHg or diastolic blood pressure of > 90 mmHg.
- •Clinically significant ECG abnormality, including a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTcF interval of > 450 msec), or had a family history of prolonged QTc syndrome or sudden death.
- •History of smoking or use of nicotine containing substances within the previous 2 months, as determined by medical history or healthy volunteer's verbal report and confirmed by cotinine test at check in for each treatment period.
- •History of drug and/or alcohol misuse prior to screening or a positive urine drug test at Screening or at Check in for each treatment period.
- •Diagnosed with acquired immune deficiency syndrome or has performed tests that are positive for human immunodeficiency virus, hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus, or pneumocystis jiroveci pneumonia.
- •Participated in a clinical trial of other drug before screening, and the time since the last use of other study drug is less than 5 times the half-life or 4 weeks, whichever is longer, or the healthy volunteer is currently enrolled in another clinical study.
- •Consumed grapefruit, starfruit, Seville oranges, or their products within 7 days prior to the first dose.
- •Consumed herbal preparations/medications, including, but not limited to, St. John's Wort, kava, ephedra (ma huang), Ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng, within 7 days prior to the first dose (21 days for St. John's Wort).
- •Experienced a weight loss or gain of >10% within 4 weeks prior to the first dose as noted by medical history and weight at screening and Check-in.
- •Received blood or blood products within 4 weeks or donated blood or blood products within 8 weeks prior to the first dose or donated double red cell within 16 weeks prior to first dose.
- •Used any over-the-counter (OTC) medications or prescription drugs (medications that can inhibit or induce CYP3A4/CYPC9, or lower gastric acid in particular) within 2 weeks prior to the first dose.
- •Allergic to any of the study drugs (or its excipients) to be given in this study.
- •Female healthy volunteer is pregnant, lactating, or breastfeeding.
- •Male healthy volunteer who plans to donate sperm or father a child within 30 days after receiving the study drug.
- •Any condition that would make him or her, in the opinion of the PI or sponsor, unsuitable for the study, or who, in the opinion of the PI, is not likely to complete the study for any reason.
- •For Part A only, participants characterized by any of the following CYP2C9 genotypes: *2/*2, *2/*3, or *3/*3.
研究组 & 干预措施
Part A - Itraconazole
Period 1 -- Participants to receive 10mg dose of HMPL-689 by mouth as a single agent treatment on Day 1
Period 2 -- Participants to receive 200mg Itraconazole by mouth twice daily beginning on Day 3 through Day 10. On Day 7 200 mg Itraconazole and 10 mg HMPL-689 will be simultaneously administered.
干预措施: Itraconazole 200 mg (Drug)
Part B - Fluconazole
Period 1 -- Participants to receive 10mg dose of HMPL-689 by mouth as a single agent treatment on Day 1
Period 2 -- Participants to receive 400mg Fluconazole by mouth daily on Day 3, then 200 mg Fluconazole by mouth daily Day 4 through Day 10. On Day 7 200 mg Fluconazole and 10 mg HMPL-689 will be simultaneously administered.
干预措施: Fluconazole 400 mg (Drug)
Part C - Rimfampin
Period 1 -- Participants to receive 30mg dose of HMPL-689 by mouth as a single agent treatment on Day 1
Period 2 -- Participants to receive 600mg Rifampin by mouth daily beginning on Day 3 through Day 11. On Day 10 600mg Rifampin will be administered by mouth approximately 1 hour before the start of breakfast and 30mg HMPL-689 will be administered by mouth approximately 30 minutes after the start of breakfast.
干预措施: Rifampin 600 mg (Drug)
Part D - Rabeprazole
Period 1 -- Participants to receive 30mg dose of HMPL-689 by mouth as a single agent treatment on Day 1
Period 2 -- Participants to receive 40mg Rabeprazole by mouth daily beginning on Day 3 through Day 9. On Day 9 40mb Rabeprazole will be administered by mouth approximately 1 hour before the start of breakfast and 30mg HMPL-689 will be administered by mouth approximately 30 minutes after the start of breakfast.
干预措施: Rabeprazole 40 mg (Drug)
结局指标
主要结局
Cmax
时间窗: From Day 1 to Day 11 (Day 12 for Rifampin)
Maximum observed plasma concentration
AUC0-inf
时间窗: From Day 1 to Day 11 (Day 12 for Rifampin)
Area under the plasma concentration-time curve from time 0 to infinity (if data permit)
AUC0-t
时间窗: From Day 1 to Day 11 (Day 12 for Rifampin)
Area under the plasma concentration-time curve from time 0 to time of the last measurable concentration
次要结局
- Incidence of AEs/SAEs(From Day 1 to Day 11 (Day 12 for Rifampin))