A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib
- Conditions
- Drug-drug Interaction
- Interventions
- Registration Number
- NCT03723395
- Lead Sponsor
- Seagen Inc.
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 116
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part D tolbutamide Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam Part B tucatinib Tucatinib plus Rifampin Part D repaglinide Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam Part A tucatinib Tucatinib plus Itraconazole Part A itraconazole Tucatinib plus Itraconazole Part B rifampin Tucatinib plus Rifampin Part C tucatinib Tucatinib plus Gemfibrozil Part C gemfibrozil Tucatinib plus Gemfibrozil Part D tucatinib Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam Part D midazolam Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam Part E tucatinib Tucatinib plus Digoxin Part E digoxin Tucatinib plus Digoxin
- Primary Outcome Measures
Name Time Method Time of maximum observed concentration 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 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).
Area under the concentration-time curve (AUC) from time 0 to infinity 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 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 volume of distribution 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).
Maximum observed concentration 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)
AUC from time 0 to the time of the last quantifiable concentration 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 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 Up to 22 days PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)
- Secondary Outcome Measures
Name Time Method Accumulation ratio Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Percentage extrapolation in AUC Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Maximum observed concentration Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Apparent volume of distribution at steady state Up to 15 days PK parameter of tucatinib; Parts D and E only
Incidence of adverse events (AEs) Up to 58 days Parts A, B, C, D, and E (all)
Time of maximum observed concentration Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Apparent terminal elimination half-life Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Apparent total clearance Up to 8 days PK parameter of tucatinib; Parts D and E only
Apparent total clearance at steady state Up to 15 days PK parameter of tucatinib; Parts D and E only
Apparent volume of distribution Up to 8 days PK parameter of tucatinib; Parts D and E only
Physical examinations Up to 58 days Incidence of AEs resulting from clinically significant findings in examination of general appearance, skin, thorax/lungs, cardiovascular system, and abdomen. Parts A, B, C, D, and E (all)
AUC within a dosing interval Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Incidence of laboratory abnormalities Up to 58 days Parts A, B, C, D, and E (all)
12-lead electrocardiogram (ECG) assessment Up to 58 days PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all)
Vital signs measurements Up to 58 days Heart rate. Parts A, B, C, D, and E (all)
AUC from time 0 to infinity Up to 8 days PK parameters of tucatinib and ONT-993; Parts D and E only
AUC from time 0 to the time of the last quantifiable concentration Up to 15 days PK parameters of tucatinib and ONT-993; Parts D and E only
Metabolite-to-parent ratio based on AUC Up to 15 days PK parameter of ONT-993; Parts D and E only
Trial Locations
- Locations (1)
Covance Clinical Research Unit
🇺🇸Dallas, Texas, United States