A Phase 1, Open-Label, Fixed-sequence, 5-part, Drug-drug Interaction Study of Tucatinib to Evaluate the Effects of CYP3A4 and CYP2C8 Inhibition and Induction on the Pharmacokinetics of Tucatinib and to Evaluate the Effects of Tucatinib on the Pharmacokinetics of Substrates of CYP3A4, CYP2C8, CYP2C9, and P-glycoprotein in Healthy Male and Female Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Seagen Inc.
- 入组人数
- 116
- 试验地点
- 1
- 主要终点
- Time of maximum observed concentration
研究概览
简要总结
This study is being done to look at how tucatinib could affect the way other drugs work. This study will look at healthy volunteers and how tucatinib affects their liver enzymes. Liver enzymes can change how drugs work in the body. There are 5 parts to this study. Parts A and C are looking at how the body breaks down tucatinib when there are lower levels of certain liver enzymes. Part B is looking at how the body breaks down tucatinib when there are high levels of certain liver and stomach enzymes. Parts D and E are looking at how tucatinib could change the levels of some liver and stomach enzymes in the body. This will help us know more about how tucatinib should be given to patients.
详细描述
This is a fixed-sequence, drug-drug interaction study of tucatinib conducted in 5 parts in healthy subjects. Part A will evaluate the effect of the strong CYP3A4 inhibitor itraconazole on the pharmacokinetics (PK) of tucatinib. Part B will evaluate the effect of rifampin, a strong inducer of CYP3A4 and CYP2C8, on the PK of tucatinib. Part C will evaluate the effect of the strong CYP2C8 inhibitor gemfibrozil on the PK of tucatinib. Part D will evaluate the effects of tucatinib on the PK of substrate probes of the metabolizing enzymes CYP2C8 (repaglinide), CYP2C9 (tolbutamide), and CYP3A4 (midazolam). Part E will evaluate the effect of tucatinib on the PK of a substrate probe of the transporter P-gp (digoxin). Parts A, B, C, D, and E of the study are independent of one another and do not need to be conducted in a particular order.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Body mass index (BMI) between 18 and 32 kg/m^2
- •In good health, determined be no clinically significant findings from medical history, physical examination, and screening evaluations
- •Female subjects must be of nonchildbearing potential
- •Male subjects must agree to use contraception or must be surgically sterile for at least 90 days prior to enrollment
- •Able to understand and sign informed consent form
排除标准
- •Any condition affecting drug absorption (including stomach or intestinal surgery)
- •Significant history of metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder
- •History of hypersensitivity, intolerance, or allergy to any drug compounds, food, or other substance (unless approved by Investigator)
- •Participation in a clinical study involving an investigational drug within the past 30 days
- •Use or intend to any prescription medications within 28 days prior to check in
- •Use of tobacco- or nicotine-containing products within 28 days prior to check in
- •History of hyperbilirubinemia
- •History of alcoholism or drug abuse within 2 years
- •History of regular alcohol consumption exceeding 7 drinks/week for female subjects or 14 drinks/week for male subjects
- •Positive hepatitis panel and/or positive human immunodeficiency virus (HIV) test
研究组 & 干预措施
Part E
Tucatinib plus Digoxin
干预措施: digoxin (Drug)
Part A
Tucatinib plus Itraconazole
干预措施: tucatinib (Drug)
Part A
Tucatinib plus Itraconazole
干预措施: itraconazole (Drug)
Part B
Tucatinib plus Rifampin
干预措施: tucatinib (Drug)
Part B
Tucatinib plus Rifampin
干预措施: rifampin (Drug)
Part C
Tucatinib plus Gemfibrozil
干预措施: tucatinib (Drug)
Part C
Tucatinib plus Gemfibrozil
干预措施: gemfibrozil (Drug)
Part D
Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam
干预措施: tucatinib (Drug)
Part D
Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam
干预措施: repaglinide (Drug)
Part D
Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam
干预措施: tolbutamide (Drug)
Part D
Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam
干预措施: midazolam (Drug)
Part E
Tucatinib plus Digoxin
干预措施: tucatinib (Drug)
结局指标
主要结局
Time of maximum observed concentration
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Area under the concentration-time curve (AUC) from time 0 to infinity
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Apparent terminal elimination half-life
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Maximum observed concentration
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Apparent total clearance
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).
Apparent volume of distribution
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).
AUC from time 0 to the time of the last quantifiable concentration
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Percentage extrapolation in AUC
时间窗: Up to 22 days
PK parameters for tucatinib (Parts A, B, and C); repaglinide and its M4 metabolite (Part D), tolbutamide and its 4-hydroxytolbutamide metabolite (Part D), midazolam and its 1-hydroxymidazolam metabolite (Part D), and digoxin (Part E)
Metabolite-to-parent ratio based on AUC
时间窗: Up to 22 days
PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)
次要结局
- Vital signs measurements(Up to 58 days)
- Accumulation ratio(Up to 15 days)
- Percentage extrapolation in AUC(Up to 15 days)
- Maximum observed concentration(Up to 15 days)
- Apparent volume of distribution at steady state(Up to 15 days)
- Incidence of adverse events (AEs)(Up to 58 days)
- Time of maximum observed concentration(Up to 15 days)
- Apparent terminal elimination half-life(Up to 15 days)
- Apparent total clearance(Up to 8 days)
- Apparent total clearance at steady state(Up to 15 days)
- Apparent volume of distribution(Up to 8 days)
- Incidence of laboratory abnormalities(Up to 58 days)
- 12-lead electrocardiogram (ECG) assessment(Up to 58 days)
- Physical examinations(Up to 58 days)
- AUC within a dosing interval(Up to 15 days)
- AUC from time 0 to infinity(Up to 8 days)
- AUC from time 0 to the time of the last quantifiable concentration(Up to 15 days)
- Metabolite-to-parent ratio based on AUC(Up to 15 days)