A Phase I, Open-label, Fixed-sequence Study to Assess the Effects of Strong CYP1A2 Inhibitor (Fluvoxamine) on Savolitinib Exposure in Healthy Male Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Maximum observed plasma (peak) drug concentration (Cmax) for savolitinib
研究概览
简要总结
This study will assess the effects of strong CYP1A2 (Cytochrome P450 1A2) inhibitor (fluvoxamine) on savolitinib exposure in healthy male subjects, performed at a single clinical unit.
详细描述
This study will be a Phase I, open-label, fixed-sequence, 2-treatment period study.
The study will consist of 2 periods. During period 1 of the study, each subject will receive a single oral dose of savolitinib following an overnight fast. A low-fat breakfast will be provided prior to dosing. There will be a minimum washout period of 10 days (14 days between two successive savolitinib doses) between period 1 and period 2.
During period 2 of the study, subject will take oral doses of fluvoxamine alone from Days 1 to 4. There would be no dietary restrictions for fluvoxamine dosing. On Day 5, subjects will take a single oral dose of savolitinib and oral dose of fluvoxamine. On Day 6, subject will receive an oral dose of fluvoxamine alone. Each subject would be involved in the study for 9 weeks (including screening window).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy subjects with suitable veins for cannulation or repeated venipuncture.
- •Male subjects must use barrier contraception.
- •Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- •Regular bowel movements.
排除标准
- •History of any clinically significant disease or disorder, which in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
- •History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
- •Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, vital signs, 12 lead ECG and physical examination.
- •QTcF > 450 ms or QT > 500 ms or other ECG abnormality making interpretation more difficult, as judged by the investigator, or a history of additional risk factors for Torsades de Points, which in the opinion of the investigator may put the subject at risk.
- •Any positive result on screening for serum hepatitis B surface antigen OR anti-HBc antibody, indicative of active hepatitis B, hepatitis C antibody, or HIV antibody.
- •History of latent or chronic infections.
- •Known or suspected drug or alcohol abuse or positive drugs of abuse test. History of excessive alcohol assumption or chronic alcohol induced disease. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
- •Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 1 month (30 days) of Visit 2 (Day -1 of Period 1) or 5 half lives whichever longer in this study or participation in a method development study (no drug) 1 month prior to Visit
- •The period of exclusion begins 1 month after the final dose or 5 half-lives after the final dose or 1 month after the last visit, whichever is the longest.
- •History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.
- •Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 6 months prior to screening.
- •Use of any prescribed or non prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies (which include but are not limited to: kava, ephedra [ma hung], ginko biloba, dehydroepiandrosterone, yohimbe, saw palmetto and ginseng), megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer (> 5 half-lives) if the medication has a long half-life.
- •Subject has clinical signs and symptoms consistent with COVID-19, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission unless confirmed by a negative SARS CoV-2 PCR test.
- •History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).
- •Excessive intake of caffeine-containing drinks or food.
- •Planned in-patient surgery, dental procedure, or hospitalization during the study.
- •Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug.
- •Received a seasonal flu vaccine (including H1N1, H1N5) 28 days prior to first dose of study drug.
研究组 & 干预措施
Savolitinib/Savolitinib+Fluvoxamine
In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone.
干预措施: Savolitinib (Drug)
Savolitinib/Savolitinib+Fluvoxamine
In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone.
干预措施: Fluvoxamine (Drug)
结局指标
主要结局
Maximum observed plasma (peak) drug concentration (Cmax) for savolitinib
时间窗: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
To evaluate the effects of fluvoxamine on savolitinib Cmax in healthy male subjects after administration of a single oral dose.
Area under plasma concentration time curve from zero to infinity (AUCinf) for savolitinib
时间窗: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
To evaluate the effects of fluvoxamine on savolitinib AUCinf in healthy male subjects after administration of a single oral dose.
次要结局
- AUClast for metabolites M2 and M3(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- AUCinf for metabolites M2 and M3(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Ratio of metabolite Cmax to parent Cmax (MRCmax)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz) for savolitinib and metabolites (M2 and M3)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Number of data points used for λz determination (λzN) for savolitinib and metabolites (M2 and M3)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Apparent total body clearance of drug from plasma after extravascular administration (CL/F) for savolitinib(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) for savolitinib(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Cmax for metabolites M2 and M3(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Ratio of metabolite AUClast to parent AUClast (MRAUClast)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Time to reach peak or maximum observed concentration or response following drug administration (tmax) for savolitinib and metabolites (M2 and M3)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz) for savolitinib and metabolites (M2 and M3)(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) for savolitinib(Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7)
- Number of subjects with adverse events (AEs)(From screening (Day -28 to Day -2) to follow up visit (approximately 9 weeks))