Healthy
Conditions
Brief summary
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.
Interventions
DRUGAbemaciclib
Administered orally
DRUGPlacebo
Administered orally
DRUGLoperamide
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | Day 1: 2hr,4hr,6hr,8hr,10hr,12hr,14hr,24hr Post Dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose | 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. |
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose | 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. |
| Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Last Time Point With Measurable Concentration [AUC(0-tlast)] 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 | Blood samples were collected from participants in Cohort 2 Period 4 (DDI) to determine plasma concentrations of Loperamide. |
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) 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 | Blood samples were collected from participants in Cohort 2 Period 4 (DDI) to determine plasma concentrations of Loperamide. |
Countries
United States
Participant flow
Recruitment details
Dose escalation study with 2 cohorts, participants in cohort 1 were randomized to 1 of 4 sequences & participants in cohort 2 were randomized to 1 of 3 sequences. Cohort 1 had periods 1 to 4 with at least 5 days washout between each dose, Cohort 2 had periods 4(DDI) to 7 with at least 8 days washout between each dose.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Single ascending doses of 200, 300, and 400 mg of Abemaciclib & Placebo were administered orally in one of the four sequences in each period. | 20 |
| Cohort 2 Single ascending doses of 400, 600 mg Abemaciclib & Placebo were administered orally in one of the four sequences in each period. Loperamide 8mg was administered orally in period 4 (DDI) along with Abemaciclib. | 15 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Period 3 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 1 | Cohort 2 |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 8.9 | 48.9 years STANDARD_DEVIATION 7.9 | 58 years STANDARD_DEVIATION 7.5 |
| Body Mass Index (BMI) | 27.12 Kilogram per square meter (Kg/m^2) STANDARD_DEVIATION 2.82 | 26.80 Kilogram per square meter (Kg/m^2) STANDARD_DEVIATION 3.15 | 27.55 Kilogram per square meter (Kg/m^2) STANDARD_DEVIATION 2.35 |
| Ethnicity Hispanic or Latino | 10 Participants | 10 Participants | 0 Participants |
| Ethnicity Not Hispanic or Latino | 25 Participants | 10 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 32 Participants | 18 Participants | 14 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 35 Participants | 20 Participants | 15 Participants |
| Sex: Female, Male Female | 28 Participants | 15 Participants | 13 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 34 | 4 / 20 | 5 / 20 | 17 / 35 | 12 / 15 | 5 / 15 | 3 / 7 | 3 / 8 |
| serious Total, serious adverse events | 0 / 34 | 0 / 20 | 0 / 20 | 0 / 35 | 0 / 15 | 0 / 15 | 0 / 7 | 0 / 8 |
Outcome results
Primary
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.
Time frame: Day 1: 2hr,4hr,6hr,8hr,10hr,12hr,14hr,24hr Post Dose
Population: All randomized participants who received at least one dose of study drug and had baseline and post baseline QTcF values.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 2hr | 1.4 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 4hr | -2.0 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 6hr | 0.6 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 8hr | 2.8 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 10hr | 2.1 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 12hr | -0.3 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 14hr | 3.9 Millisecond (msec) |
| 200 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 24hr | 1.4 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 12hr | -0.7 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 10hr | 1.3 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 4hr | 0.8 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 24hr | 4.2 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 14hr | 3.3 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 8hr | 2.7 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 6hr | -0.2 Millisecond (msec) |
| 300 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 2hr | 3.3 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 14hr | 1.0 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 6hr | -1.8 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 8hr | 2.2 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 10hr | 1.5 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 12hr | -0.5 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 24hr | -0.4 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 2hr | 0.2 Millisecond (msec) |
| 400 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 4hr | -0.7 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 6hr | -3.7 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 8hr | 2.8 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 4hr | -4.2 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 2hr | -2.1 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 10hr | 5.9 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 24hr | 0.9 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 14hr | 2.3 Millisecond (msec) |
| 600 mg Abemaciclib | Mean Time Matched Placebo-Adjusted Changes From Baseline For Fridericia's Corrected QT Interval (ΔΔQTcF) | 12hr | 4.4 Millisecond (msec) |
Secondary
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.
Time frame: Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose
Population: All randomized participants who received at least one dose of study drug in Cohort 1 all periods \& Cohort 2 periods 5,6, and 7 with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | 3560 ng*hr/mL | Geometric Coefficient of Variation 38 |
| 300 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | 5210 ng*hr/mL | Geometric Coefficient of Variation 37 |
| 400 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | 7610 ng*hr/mL | Geometric Coefficient of Variation 46 |
| 600 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | 14600 ng*hr/mL | Geometric Coefficient of Variation 42 |
| 400 mg Abemaciclib + Loperamide 8mg | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time 0 to Last Time Point With Measurable Concentration AUC(0-tlast) of Abemaciclib | 9420 ng*hr/mL | Geometric Coefficient of Variation 57 |
Secondary
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.
Time frame: 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
Population: All randomized participants in Cohort 2 Period 4 (DDI) who received Loperamide \& had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Last Time Point With Measurable Concentration [AUC(0-tlast)] of Loperamide | 46.1 ng*hr/mL | Geometric Coefficient of Variation 47 |
| 300 mg Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Last Time Point With Measurable Concentration [AUC(0-tlast)] of Loperamide | 47.3 ng*hr/mL | Geometric Coefficient of Variation 53 |
Secondary
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.
Time frame: Day 1: 2, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 120 hours Post Dose
Population: All randomized participants who received at least one dose of study drug in Cohort 1 all periods \& Cohort 2 periods 5,6, and 7 with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | 102 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 31 |
| 300 mg Abemaciclib | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | 130 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 40 |
| 400 mg Abemaciclib | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | 182 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 42 |
| 600 mg Abemaciclib | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | 308 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 45 |
| 400 mg Abemaciclib + Loperamide 8mg | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | 199 Nanogram per Milliliter (ng/mL) | Geometric Coefficient of Variation 55 |
Secondary
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.
Time frame: 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
Population: All randomized participants in Cohort 2 Period 4 (DDI) who received Loperamide \& had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Loperamide | 1.83 ng/mL | Geometric Coefficient of Variation 56 |
| 300 mg Abemaciclib | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Loperamide | 2.17 ng/mL | Geometric Coefficient of Variation 49 |