A Study of Abemaciclib in Healthy Participants

Study Overview
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Brief Summary
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The purposes of this study are to determine: The effect of single increasing doses of the study drug, abemaciclib, on healthy participants. The relationship between the amount of abemaciclib and the electrical tracing of the heart rhythm when abemaciclib is given. How much abemaciclib is found in the bloodstream and how long the body takes to get rid of it. Information about any side effects that occur will be collected. The study will enroll two groups (cohorts) of participants. Each group will complete 4 study periods. This study is expected to last about 3 months. Screening may occur up to 28 days prior to enrollment. All participants will undergo a follow-up assessment approximately 21 days after administration of their final dose of study drug.

Official Title
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A Randomized, Single-Blind, Placebo-Controlled, Single Ascending Dose Study to Determine the Exposure-Response Relationship Between Abemaciclib and QT Interval in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Abemaciclib
* Drug: Placebo
* Drug: Loperamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overtly healthy males or females, as determined by medical history and physical examination Male participants will be sterile Female participants must not be of childbearing potential Exclusion Criteria: Have known allergies to abemaciclib, related compounds, or any components of the formulation Have an abnormality in the 12-lead electrocardiogram (ECG) including a Fridericia's corrected QT interval (QTcF) greater than 450 milliseconds (ms) (males) or greater than 470 ms (females) Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs Have a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, and diarrhea, or malabsorption syndromes, or constipation Additional Exclusion Criterion for Participants Enrolled in Cohort 2: Have a known hypersensitivity to loperamide hydrochloride or to any of the excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abemaciclib<br>200 - 600 mg single increasing oral dose of abemaciclib on Day 1 of up to 3 study periods. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;|
| Placebo Comparator: Placebo<br>Single oral dose of placebo on Day 1 of 1 study period. | Drug: Placebo<br>* Administered orally<br>|
| Active Comparator: Loperamide<br>Cohort 2, only. 8 mg Loperamide given orally once in 1 of 4 study periods. | Drug: Loperamide<br>* Administered orally<br>|
| Experimental: Loperamide + Abemaciclib<br>Cohort 2, only. 8 mg Loperamide co-administered with abemaciclib given orally once in up to 1 of 4 study periods. | Drug: Abemaciclib<br>* Administered orally<br>* Other names: LY2835219;Drug: Loperamide<br>* Administered orally<br>|
| Active Comparator: Loperamide + Placebo<br>Cohort 2, only. 8 mg Loperamide co-administered with placebo given orally once in up to 1 of 4 study periods. | Drug: Placebo<br>* Administered orally<br>Drug: Loperamide<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data. ECG monitoring was conducted using a 12-lead digital Holter recorder from approximately 2 hours predose through 24 hours postdose on Day 1 of each period using 12-lead digital Holter recorder. Fridericia-corrected QT interval (QTcF): QTcF = QT/RR1/3, where RR is the interval between two R waves. | Day 1: 2hr,4hr,6hr,8hr,10hr,12hr,14hr,24hr Post Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | Blood samples were collected from participants in Cohort 1(all periods) and Cohort 2 (Periods 5, 6, and 7) to determine the plasma concentrations of Abemaciclib. | Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose | 
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | Blood samples were collected from participants in Cohort 1(all periods) and Cohort 2 (Periods 5, 6, and 7) to determine the plasma concentrations of Abemaciclib 0-tlast. | Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose | 
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Last Time Point With Measurable Concentration [AUC(0-tlast)] of Loperamide | Blood samples were collected from participants in Cohort 2 Period 4 (DDI) to determine plasma concentrations of Loperamide. | Day -3: Predose, 1, 2, 4, 6, 8, 12, 14, 24, and 48 hours postdose;Day 1 predose, (-0.25 hours), and Day1: 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, and 72 hours Post Dose | 
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Loperamide | Blood samples were collected from participants in Cohort 2 Period 4 (DDI) to determine plasma concentrations of Loperamide. | Day -3: Predose,1, 2, 4, 6, 8, 12, 14, 24, and 48 hours postdose;Day 1 predose, (-0.25 hours), and Day1: 1, 2, 4, 6, 8, 10, 12, 14, 24, 48, and 72 hours Post Dose |