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

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

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.

Study Overview

• Status: Completed
• Conditions: Drug-drug Interaction
• Intervention / Treatment: Drug: tucatinib; Drug: itraconazole; Drug: rifampin; Drug: gemfibrozil; Drug: repaglinide; Drug: tolbutamide; Drug: midazolam; Drug: digoxin

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.

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Covance Clinical Research Unit
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A; Tucatinib plus Itraconazole	Drug: tucatinib; 300mg dose, orally administered; Drug: itraconazole; 200mg dose
Experimental: Part B; Tucatinib plus Rifampin	Drug: tucatinib; 300mg dose, orally administered; Drug: rifampin; 600mg dose
Experimental: Part C; Tucatinib plus Gemfibrozil	Drug: tucatinib; 300mg dose, orally administered; Drug: gemfibrozil; 600mg tablets
Experimental: Part D; Tucatinib plus Repaglinide plus Tolbutamide plus Midazolam	Drug: tucatinib; 300mg dose, orally administered; Drug: repaglinide; 1mg dose; Drug: tolbutamide; 500mg dose; Drug: midazolam; 2mg dose
Experimental: Part E; Tucatinib plus Digoxin	Drug: tucatinib; 300mg dose, orally administered; Drug: digoxin; 0.5 mg dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Up to 22 days
AUC from time 0 to the time of the last quantifiable concentration	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)	Up to 22 days
Percentage extrapolation in AUC	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)	Up to 22 days
Maximum observed concentration	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)	Up to 22 days
Time of maximum observed concentration	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)	Up to 22 days
Apparent terminal elimination half-life	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)	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).	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).	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)	Up to 22 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs)	Parts A, B, C, D, and E (all)	Up to 58 days
Incidence of laboratory abnormalities	Parts A, B, C, D, and E (all)	Up to 58 days
12-lead electrocardiogram (ECG) assessment	PR, RR, QRS, and QT interval. Parts A, B, C, D, and E (all)	Up to 58 days
Vital signs measurements	Oral temperature. Parts A, B, C, D, and E (all)	Up to 58 days
Vital signs measurements	Respiratory rate. Parts A, B, C, D, and E (all)	Up to 58 days
Vital signs measurements	Blood pressure (systolic and diastolic). Parts A, B, C, D, and E (all)	Up to 58 days
Vital signs measurements	Heart rate. Parts A, B, C, D, and E (all)	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)	Up to 58 days
AUC within a dosing interval	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
AUC from time 0 to infinity	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 8 days
AUC from time 0 to the time of the last quantifiable concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Percentage extrapolation in AUC	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Maximum observed concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Time of maximum observed concentration	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Apparent terminal elimination half-life	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Apparent total clearance	PK parameter of tucatinib; Parts D and E only	Up to 8 days
Apparent total clearance at steady state	PK parameter of tucatinib; Parts D and E only	Up to 15 days
Apparent volume of distribution	PK parameter of tucatinib; Parts D and E only	Up to 8 days
Apparent volume of distribution at steady state	PK parameter of tucatinib; Parts D and E only	Up to 15 days
Accumulation ratio	PK parameters of tucatinib and ONT-993; Parts D and E only	Up to 15 days
Metabolite-to-parent ratio based on AUC	PK parameter of ONT-993; Parts D and E only	Up to 15 days

Collaborators and Investigators

• Sponsor: Seagen Inc.
• Investigators: Study Director: Alex Vo, PhD, Seagen Inc.

Publications and helpful links

General Publications

• Topletz-Erickson A, Lee A, Rustia EL, Sun H, Mayor JG, Abdulrasool LI, Walker L, Endres CJ. Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers. Clin Pharmacokinet. 2022 Oct;61(10):1417-1426. doi: 10.1007/s40262-022-01144-z. Epub 2022 Aug 6.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2018
• Primary Completion (Actual): December 21, 2018
• Study Completion (Actual): December 28, 2018

Study Registration Dates

• First Submitted: October 24, 2018
• First Submitted That Met QC Criteria: October 25, 2018
• First Posted (Actual): October 29, 2018

Study Record Updates

• Last Update Posted (Actual): December 18, 2019
• Last Update Submitted That Met QC Criteria: December 16, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Central Nervous System Depressants; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antimetabolites; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Cardiotonic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP2C8 Inhibitors; Digoxin; Midazolam; Rifampin; Itraconazole; Tucatinib; Gemfibrozil; Tolbutamide; Repaglinide
• Other Study ID Numbers: ONT-380-012

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No