Major Depressive Disorder
Conditions
Brief summary
The purpose of this study is to determine how warfarin might affect LY2216684 and how giving LY2216684 might affect warfarin in the body. Information about any side effects that may occur will also be collected.
Interventions
DRUGWarfarin
10-mg warfarin oral dose
DRUGLY2216684
18-mg LY2216684 oral dose
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Are overtly healthy, as determined by medical history and physical examination * Male participants - Agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug * Female participants - Are women of child-bearing potential who test negative for pregnancy at the time of enrollment, have used a reliable method of birth control for 6 weeks prior to administration of study drug, and agree to use a reliable method of birth control during the study and for 1 month following the last dose of study drug; or women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause (at least 1 year without menses or 6 months without menses and a follicle stimulating hormone \[FSH\] \>40 mass International Units per milliliter \[mIU/mL\]) * Have body weight \>50 kilogram (kg) * Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator * Have venous access sufficient to allow blood sampling as per the protocol * Have normal blood pressure and pulse rate (sitting position) as determined by the investigator * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures * Have given written informed consent approved by Lilly and the ethical review board (ERB) governing the site * Are cytochrome P450 2C9 (CYP2C9) extensive metabolizers, as determined by genotyping assessment
Exclusion criteria
* Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device other than the study drug, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have known allergies to LY2216684, warfarin, or related compounds * Are persons who have previously completed or withdrawn from this study or any other study investigating LY2216684 within 6 months prior to screening * Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study * Have a history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data * Have a history or show evidence of significant active neuropsychiatric disease, or have a history of suicide attempt or ideation * Regularly use known drugs of abuse and/or show positive findings on urinary drug screening * Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies * Show evidence of hepatitis C and/or positive hepatitis C antibody * Show evidence of hepatitis B and/or positive hepatitis B surface antigen * Are women with a positive pregnancy test or women who are lactating * Intend to use over-the-counter or prescription medication (including hormonal contraceptives) within 14 days prior to dosing unless deemed acceptable by the investigator and sponsor's medical monitor * Use of any drugs or substances that are known to be substrates, inducers, or inhibitors of cytochrome P450 2C19 (CYP2C19) or CYP2C9 within 30 days prior to dosing * Have donated blood of more than 500 mL within the last month * Have an average weekly alcohol intake that exceeds 14 units per week, or are unwilling to stop alcohol consumption 48 hours prior to dosing in each period and while resident at the CRU (1 unit = 12 ounces \[oz\] or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits) * Consume 5 or more cups of coffee (or other beverages of comparable caffeine content) per day, on a habitual basis, or any subjects unwilling to adhere to study caffeine restrictions * Have used any tobacco-containing or nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to enrollment * Have consumed grapefruit or grapefruit-containing products 7 days prior to enrollment and during the study. * Have a documented or suspected history of glaucoma * History or presence of significant bleeding disorders; that is, hematemesis, melanena, severe or recurrent epistaxis, hemoptysis, clinically overt hematuria or intracranial hemorrhage * Subjects with a history of gastrointestinal ulcers or hemorrhage * Personal or family history of coagulation or bleeding disorders or reasonable suspicion of vascular malformations; for example, cerebral hemorrhage, aneurysm, or premature stroke (cerebrovascular accident \<65 years of age) * Self-reported history of increased bleeding from trauma (for example, prolonged bleeding after tooth extraction) * History of major surgery within 3 months of screening * Planned surgery within 14 days after the last day of dosing * International normalized ratio/prothrombin time (INR/PT), or activated partial thromboplastin time (APTT) above the normal reference range at screening * Positive fecal occult blood examination at screening * Female subjects with a history of menorrhagia * Subjects determined to be unsuitable by the investigator for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | Least Squares (LS) geometric mean was based on Cmax of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
| Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | This outcome was measured based on Tmax of S-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | Least Squares (LS) geometric mean was based on AUC0-∞ of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | Least Squares (LS) geometric mean was based on Cmax of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
| Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin | Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3 | This outcome was measured based on Tmax of R-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test). |
| Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin | Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3 | The INR is the ratio of a participant's prothrombin time to a normal (control) sample. AUCINR was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
| Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax) | Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3 | INR is the ratio of a participant's prothrombin time to a normal (control) sample. INRmax was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Warfarin, LY2216684 + Warfarin Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 1 | Protocol Violation | 2 |
| Period 2 | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Warfarin, LY2216684 + Warfarin |
|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 6.6 |
| Race/Ethnicity, Customized Black or African American | 6 Participants |
| Race/Ethnicity, Customized Multiple | 4 Participants |
| Race/Ethnicity, Customized White | 8 Participants |
| Region of Enrollment United States | 18 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 10 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 | 8 / 16 | 6 / 18 | 8 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 18 | 0 / 16 |
Outcome results
Primary
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin
Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin | 22200 nanogram*hour per milliliter (ng*hr/mL) |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin | 20800 nanogram*hour per milliliter (ng*hr/mL) |
90% CI: [1, 1.13]Mixed Models Analysis
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin
Least Squares (LS) geometric mean was based on Cmax of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin | 633.00 nanogram per milliliter (ng/mL) |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin | 566.57 nanogram per milliliter (ng/mL) |
90% CI: [1.07, 1.16]Mixed Models Analysis
Primary
Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin
This outcome was measured based on Tmax of S-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and had evaluable concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin | 3.00 hour (h) |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin | 3.00 hour (h) |
p-value: 0.955190% CI: [-0.5, 0.5]Wilcoxon (Mann-Whitney)
Secondary
Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin
The INR is the ratio of a participant's prothrombin time to a normal (control) sample. AUCINR was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin | 155 ratio |
| 10 mg Warfarin Alone (Reference) | Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin | 149 ratio |
Comparison: Least Squares (LS) geometric mean was based on pharmacodynamic AUCINR of warfarin.90% CI: [1.02, 1.05]Mixed Models Analysis
Secondary
Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax)
INR is the ratio of a participant's prothrombin time to a normal (control) sample. INRmax was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax) | 1.19 ratio |
| 10 mg Warfarin Alone (Reference) | Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax) | 1.14 ratio |
Comparison: Least Squares (LS) geometric mean was based on pharmacodynamic INRmax of warfarin.90% CI: [1.01, 1.08]Mixed Models Analysis
Secondary
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin
Least Squares (LS) geometric mean was based on AUC0-∞ of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin | 43600 ng*h/mL |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin | 38000 ng*h/mL |
90% CI: [1.1, 1.2]Mixed Models Analysis
Secondary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin
Least Squares (LS) geometric mean was based on Cmax of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin | 669.25 ng/mL |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin | 592.38 ng/mL |
90% CI: [1.09, 1.17]Mixed Models Analysis
Secondary
Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin
This outcome was measured based on Tmax of R-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
Time frame: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin | 3.02 h |
| 10 mg Warfarin Alone (Reference) | Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin | 4.00 h |
p-value: 0.609490% CI: [-0.5, 0.02]Wilcoxon (Mann-Whitney)