A PK Study to Assess the Drug-drug Interaction of a Strong CYP2C8 Inhibitor on Adagrasib

Study Overview
=================
Brief Summary
-----------------
A Phase 1, Open-label, Multiple-dose, One-sequence Crossover Study to Investigate the Effect of Repeated Oral Doses of a Strong CYP2C8 Inhibitor on the Steady-state Pharmacokinetics of Adagrasib in Healthy Adult Subjects

Official Title
-----------------
A Phase 1, Open-label, Multiple-dose, One-sequence Crossover Study to Investigate the Effect of Repeated Oral Doses of a Strong CYP2C8 Inhibitor on the Steady-state Pharmacokinetics of Adagrasib in Healthy Adult Subjects

Conditions
-----------------
Healthy Adults

Intervention / Treatment
-----------------
* Drug: Treatment A
* Drug: Treatment B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females, of any race, between 18 and 60 years of age, inclusive, at Screening. Body mass index between 18.0 and 32.0 kg/m2, inclusive, at Screening. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, or clinical laboratory evaluations at Screening and Check-in as assessed by the Investigator. Females of childbearing potential will not be pregnant or lactating and must have a negative result on an approved pregnancy test at Screening and Check-in. Females of childbearing potential must agree to use contraception. Male subjects must agree to use contraception. Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions. Exclusion Criteria: Significant history or clinical manifestation of any metabolic, allergic, dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, any components of the investigational product (IP), or other substance (not including seasonal allergies). History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions (eg, uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications. Significant history or clinical manifestation of any hepatic disease. History or current diagnosis of uncontrolled or significant cardiac disease. Ventricular dysfunction or history of risk factors for Torsades de Pointes. History of allergic reaction to fibric acid derivatives. History of drug abuse within 2 years prior to Screening. History of alcohol abuse within 12 months prior to Screening. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in. Use of any drugs or substances known or suspected to alter drug absorption, distribution, metabolism, or elimination. Use or intend to use any prescription medications/products within 14 days prior to Check-in. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to Check-in. Participation in a clinical study involving administration of an investigational drug in the past 30 days or 5 half-lives prior to dosing, whichever is longer. Have previously completed or withdrawn from this study or any other study investigating adagrasib, and have previously received the IP. Receipt of blood products within 3 months prior to Check-in. Donation of blood from 56 days prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Subjects who, in the opinion of the Investigator, should not participate in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A Phase 1, Open-label, Multiple-dose, One-sequence Crossover Study to Investigate the Effect of Repeated Oral Doses of a Strong CYP2C8 Inhibitor on the Steady-state Pharmacokinetics of Adagrasib in Healthy Adult Subjects
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Treatment A|Oral adagrasib 200 mg twice daily (BID) for 8 days (Days 1 to 8). Predose PK blood samples for the measurement of adagrasib concentration will be collected on Days 2 to 7. Serial PK blood samples for adagrasib will be collected up to 12 hours postdose on Days 1 and 8.|
|Drug: Treatment B|Oral adagrasib 200 mg BID and gemfibrozil 600 mg BID for 10 days (Days 9 to 18), with no evening dose of adagrasib or gemfibrozil on Day 18. Predose PK blood samples for the measurement of adagrasib concentration will be collected on Days 9 to 17 before the morning dose of adagrasib. Predose PK blood samples for the measurement of gemfibrozil trough concentration will be collected on Days 15 to 18 before the morning dose of gemfibrozil. Serial PK blood samples for adagrasib will be collected up to 12 hours postdose on Day 18.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - AUC (adagrasib) | Area under the plasma concentration time curve (AUC) during a dosage interval (AUCtau) | Days 1, 8, and 18 | 
| Pharmacokinetics - Cmax (adagrasib) | Maximum observed plasma concentration | Days 1, 8, and 18 | 
| Pharmacokinetics - Tmax (adagrasib) | Time to reach Cmax (tmax) | Days 1, 8, and 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Incidence and severity of AEs | Up to 9 weeks from screening |