Drug-drug Interaction
Conditions
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.
Interventions
DRUGgemfibrozil
600mg tablets
DRUGrepaglinide
1mg dose
DRUGtolbutamide
500mg dose
DRUGmidazolam
2mg dose
DRUGdigoxin
0.5 mg dose
DRUGtucatinib
300mg dose, orally administered
DRUGitraconazole
200mg dose
DRUGrifampin
600mg dose
Sponsors
Seagen Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
| 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) |
| 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 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 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). |
| 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). |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Maximum observed concentration | Up to 15 days | PK parameters of tucatinib and ONT-993; Parts D and E only |
| 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 |
| Incidence of adverse events (AEs) | Up to 58 days | Parts A, B, C, D, and E (all) |
| Apparent volume of distribution | Up to 8 days | PK parameter of tucatinib; 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 |
| Accumulation ratio | 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 |
| Apparent total clearance at steady state | Up to 15 days | PK parameter of tucatinib; 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 | Oral temperature. Parts A, B, C, D, and E (all) |
| 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 |
| 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 |
| Percentage extrapolation in AUC | Up to 15 days | PK parameters of tucatinib and ONT-993; Parts D and E only |
Countries
United States
Outcome results
None listed