A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib

Seagen Inc.116 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Area under the concentration-time curve (AUC) from time 0 to infinity

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 frame: Up to 22 days

AUC from time 0 to the time of the last quantifiable concentration

Time frame: Up to 22 days

Percentage extrapolation in AUC

Time frame: Up to 22 days

Maximum observed concentration

Time frame: Up to 22 days

Time of maximum observed concentration

Time frame: Up to 22 days

Apparent terminal elimination half-life

Time frame: Up to 22 days

Apparent total clearance

PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).

Time frame: Up to 22 days

Apparent volume of distribution

PK parameters for tucatinib (Parts A, B, and C); repaglinide (Part D), tolbutamide (Part D), midazolam (Part D), and digoxin (Part E).

Time frame: Up to 22 days

Metabolite-to-parent ratio based on AUC

PK parameters for M4 metabolite, 4-hydroxytolbutamide metabolite, and 1-hydroxymidazolam metabolite (Part D only)

Time frame: Up to 22 days

Secondary Outcomes

Incidence of adverse events (AEs)

Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Incidence of laboratory abnormalities

Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

12-lead electrocardiogram (ECG) assessment

PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Vital signs measurements

Oral temperature. Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Vital signs measurements

Respiratory rate. Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Vital signs measurements

Blood pressure (systolic and diastolic). Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Vital signs measurements

Heart rate. Parts A, B, C, D, and E (all)

Time frame: Up to 58 days

Physical examinations

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)

Time frame: Up to 58 days

AUC within a dosing interval

PK parameters of tucatinib and ONT-993; Parts D and E only

Time frame: Up to 15 days

AUC from time 0 to infinity

A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes