Healthy
Conditions
Brief summary
The purpose of this study is to look at how much warfarin gets into the blood stream and how long it takes the body to get rid of it when given both with and without lanabecestat. Another purpose is to evaluate the effectiveness of warfarin therapy to prevent blood clots when given with lanabecestat by measuring international normalized ratio (INR). INR measures the time it takes for blood to clot and compares it to an average. Information about any side effects that may occur will also be collected. The study will last about 5 weeks from the first dose to follow-up for each participant.
Interventions
DRUGLanabecestat
Administered orally
DRUGWarfarin
Administered orally
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male participants: will be sterile (including vasectomy) or agree to use an effective method of birth control and will not donate sperm during the study and for 3 months following the last dose of the investigational product * Female participants: women not of childbearing potential
Exclusion criteria
* Have a history of or current, significant ophthalmic disease, as determined by the investigator or ophthalmologist * Have vitiligo or any other clinically significant disorder of skin pigmentation as determined by the investigator or dermatologist * Have a history or presence of significant bleeding disorders * Have a history of gastrointestinal ulcers with hemorrhage * Have a personal or family history of coagulation or bleeding disorders or reasonable suspicion of vascular malformations * Self-reported history of increased bleeding from trauma * Have a history of major head trauma (with loss of consciousness) within the past year or minor head trauma (without loss of consciousness) within the last 3 months prior to screening * History of major surgery within 3 months of screening * Planned surgery within 14 days after the last day of dosing * International Normalized Ratio (INR)/ Prothrombin Time (PT) or activated partial thromboplastin time above the normal reference range at screening * Abnormal Protein S antigen and/or Protein C activity as determined by the investigator * History of deep vein thrombosis and/or pulmonary embolism
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound S-Warfarin | Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22 |
| Pharmacokinetics (PK): Area Under the Concentration Curve 0-∞ (AUC) of Unbound S-Warfarin | Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22 |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound R-Warfarin | Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22 |
| Pharmacokinetics (PK): Area Under The Concentration Curve 0-∞(AUC) of Unbound R-Warfarin | Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96,120, and 144 hours after administration of warfarin on Days 1 and 22 |
| Pharmacodynamics (PD): Area Under the International Normalized Ratio (INR) Versus Time Curve (AUCINR) of Warfarin | Predose, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22 |
| Pharmacodynamics (PD): Maximum Observed INR Response (INRmax) of Warfarin | Predose, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Overall study population. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 - LY3314814 and Warfarin | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 42.9 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 15 | 1 / 15 | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Pharmacokinetics (PK): Area Under the Concentration Curve 0-∞ (AUC) of Unbound S-Warfarin
Time frame: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacokinetics (PK): Area Under the Concentration Curve 0-∞ (AUC) of Unbound S-Warfarin | 108 nanogram * hour per milliliter(ng*h/mL) | Geometric Coefficient of Variation 18 |
| LY3314814 + Warfarin | Pharmacokinetics (PK): Area Under the Concentration Curve 0-∞ (AUC) of Unbound S-Warfarin | 123 nanogram * hour per milliliter(ng*h/mL) | Geometric Coefficient of Variation 19 |
Primary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound S-Warfarin
Time frame: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound S-Warfarin | 3.50 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 12 |
| LY3314814 + Warfarin | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound S-Warfarin | 3.73 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 14 |
Secondary
Pharmacodynamics (PD): Area Under the International Normalized Ratio (INR) Versus Time Curve (AUCINR) of Warfarin
Time frame: Predose, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug and had evaluable pharmacodynamic INR data on Day 22 of Period 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacodynamics (PD): Area Under the International Normalized Ratio (INR) Versus Time Curve (AUCINR) of Warfarin | 160 ng*h/mL | Geometric Coefficient of Variation 9 |
| LY3314814 + Warfarin | Pharmacodynamics (PD): Area Under the International Normalized Ratio (INR) Versus Time Curve (AUCINR) of Warfarin | 158 ng*h/mL | Geometric Coefficient of Variation 6 |
Secondary
Pharmacodynamics (PD): Maximum Observed INR Response (INRmax) of Warfarin
Time frame: Predose, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug and had evaluable pharmacodynamic INR data on Day 22 of Period 2.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacodynamics (PD): Maximum Observed INR Response (INRmax) of Warfarin | 1.29 ng/mL | Geometric Coefficient of Variation 18 |
| LY3314814 + Warfarin | Pharmacodynamics (PD): Maximum Observed INR Response (INRmax) of Warfarin | 1.26 ng/mL | Geometric Coefficient of Variation 12 |
Secondary
Pharmacokinetics (PK): Area Under The Concentration Curve 0-∞(AUC) of Unbound R-Warfarin
Time frame: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96,120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacokinetics (PK): Area Under The Concentration Curve 0-∞(AUC) of Unbound R-Warfarin | 262 ng*h/mL | Geometric Coefficient of Variation 18 |
| LY3314814 + Warfarin | Pharmacokinetics (PK): Area Under The Concentration Curve 0-∞(AUC) of Unbound R-Warfarin | 296 ng*h/mL | Geometric Coefficient of Variation 18 |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound R-Warfarin
Time frame: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after administration of warfarin on Days 1 and 22
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound R-Warfarin | 4.45 ng/mL | Geometric Coefficient of Variation 11 |
| LY3314814 + Warfarin | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Unbound R-Warfarin | 4.80 ng/mL | Geometric Coefficient of Variation 14 |