A Phase I, Fixed-sequence, Open-label Study to Assess the Effects of Savolitinib on the Pharmacokinetics of Substrates of Human Transporters Digoxin (P-gp), Rosuvastatin (OATP1B1/3), Metformin (OCT2, MATE1/2K), and Furosemide (OAT1/3) 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
- 6
- 试验地点
- 1
- 主要终点
- Plasma Area under the concentration-curve from zero to the last quantifiable concentration (AUClast) of the drug cocktail components
研究概览
简要总结
This study will assess the effects of savolitinib on the pharmacokinetics (PK) of substrates of human transporters digoxin (P-gp), rosuvastatin (OATP1B1/3), metformin (OCT2, MATE1/2K), and furosemide (OAT1/3) in healthy male subjects, performed at a single clinical unit.
详细描述
This study will be performed at a single clinical unit.
Subjects will be admitted to the clinical unit on Day -1 of Period 1 and Period 2. Subjects will have a washout period of 14 days between Period 1 and Period 2.
Period 1: Subjects will recieve a single dose of a drug cocktail of 4 medications (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E).
Period 2: Participants will receive savolitinib (Dose A) in combination with the drug cocktail of 4 medications as received in Period 1.
The study will consist of 4 visits:
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
- •Male subjects must use barrier contraception (condoms) during sexual intercourse with a female partner of childbearing potential during the study and for 6 months after the last dose of the IMPs investigational medical products (IMPs).
- •Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- •Regular bowel movements (ie, on average production of at least 1 stool per day).
排除标准
- •History of any clinically significant disease or disorder
- •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 abnormalities in clinical chemistry, hematology, or urinalysis results.
- •Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and/or first admission to the clinical unit, as judged by the investigator.
- •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 (eg heart failure, hypokalemia, family history of long QT syndrome), 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 (ie, subjects with positive anti-HBc antibody result are acceptable if anti HBc IgM antibodies are negative), hepatitis C antibody, and HIV antibody.
- •History of latent or chronic infections (eg, tuberculosis, recurrent sinusitis, genital herpes, urinary tract infections) or at risk of infection.
- •Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months (12 weeks) or within 5 half-lives of the drug, whichever is longer, of Visit 2 (Day -1 of Period 1) in this study or participation in a method development study (no drug) 1 month prior to Visit
- •The period of exclusion ends 3 months after the final dose or after 5 elimination half-lives of the drug or 1 month after the last visit, whichever is the longer.
- •History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to savolitinib, or drug cocktail medications or their excipients.
- •Subject has clinical signs and symptoms consistent with Coronavirus disease (COVID-19), eg, fever, dry cough, dyspnea, sore throat, fatigue, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission unless confirmed by a negative severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test (SARS-CoV-2 PCR test).
- •Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
- •Positive screen for drugs of abuse or cotinine at screening or on each admission to the clinical unit or positive screen for alcohol on each admission to the clinical unit.
研究组 & 干预措施
Drug cocktail/Savolitinib + Drug cocktail
Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.
干预措施: Savolitinib (Drug)
Drug cocktail/Savolitinib + Drug cocktail
Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.
干预措施: Digoxin (Drug)
Drug cocktail/Savolitinib + Drug cocktail
Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.
干预措施: Metformin Hydrochloride (Drug)
Drug cocktail/Savolitinib + Drug cocktail
Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.
干预措施: Rosuvastatin (Drug)
Drug cocktail/Savolitinib + Drug cocktail
Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.
干预措施: Furosemide (Drug)
结局指标
主要结局
Plasma Area under the concentration-curve from zero to the last quantifiable concentration (AUClast) of the drug cocktail components
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate AUClast of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)
Plasma Area Under Concentration-time Curve from zero to infinity (AUCinf) of the drug cocktail components
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate AUCinf of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)
Maximum observed plasma drug concentration (Cmax) of drug cocktail components
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate Cmax of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in the presence and absence of savolitinib
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate AUCinf ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
Plasma partial area under the concentration-time curve from time 0 to time t post-dose (AUC(0-t)) of the drug cocktail components
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate (AUC(0-t)) of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
The ratio of plasma AUC(0-t) (R AUC(0-t)) of the drug cocktail components in the presence and absence of savolitinib
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate AUC(0-t) ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
The ratio of plasma Cmax (R Cmax) of drug cocktail components in the presence and absence of savolitinib
时间窗: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
To evaluate Cmax ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
次要结局
- Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUCinflast) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Partial area under the concentration-time curve from time 0 to time t post-dose (AUC(0-t)) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Number of participants with adverse events(Day 1 in Periods 1 (Week 1) and 2 (Week 4) to Day 7 (follow-up after last Pharmacokinetic (PK) sample))
- Observed lowest concentration before the next dose is administered (Ctrough) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Plasma terminal elimination half-life (t½λz) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Cumulative amount of unchanged drug excreted into urine (Ae) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Cumulative amount of unchanged drug excreted into the urine from time 0 to time t (Ae(0-t)) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Plasma Apparent total body clearance (CL/F) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Renal clearance (CLR) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Percentage of dose excreted unchanged in urine from time 0 to t (fe(0-t)) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Cumulative amount of unchanged drug excreted into urine (CumAe) of the cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Maximum observed plasma (peak) drug concentration (Cmax) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Plasma terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))
- Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Apparent volume of distribution based on the terminal phase (Vz/F) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Apparent total body clearance (CL/F) of savolitinib and its metabolites (M2 and M3)(Day 1 and Day 2 in Period 2 (Week 4))
- Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components(Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4))