Major Depressive Disorder
Conditions
Brief summary
The purpose of this study is to measure how much of the study drugs (clopidogrel and LY2216684) reach the blood stream and how long it takes the body to dispose of them and to determine how clopidogrel and LY2216684 might affect each other in the body. Information about any side effects that may occur will also be collected.
Detailed description
Clopidogrel is rapidly converted to R-130964 by the enzyme cytochrome P450 2C19 (CYP2C19). Enrollment in the study was limited to participants with specific genotypes of the CYP2C19 gene, including the \*1/\*1 genotype (CYP2C19 extensive metabolizers) and the \*1/\*17 or \*17/\*17 genotypes (CYP2C19 ultra-rapid metabolizers). All primary and secondary objectives were limited to participants with the CYP2C19\*1/\*1 genotype.
Interventions
DRUGClopidogrel
DRUGLY2216684
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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 - 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 milli-international units per milliliter \[mIU/mL\]). * Have a body weight \>50 kilograms (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 (CYP) 2C19 extensive metabolizers or ultra -rapid 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, clopidogrel, 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 of 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 within 14 days prior to dosing unless deemed acceptable by the investigator and Sponsor's medical monitor, except for influenza vaccinations. * Use of any drugs or substances that are known to be substrates, inducers, or inhibitors of CYP2C19 or CYP3A4 within 30 days prior to dosing. * Have donated blood of more than 500 milliliters (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 check-in until completion of the study (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 participants 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, haematemesis, melanena, severe or recurrent epistaxis, haemoptysis, clinically overt clinical haematuria or intracranial haemorrhage. * Participants with a history of gastrointestinal ulcers or haemorrhage. * Personal or family history of coagulation or bleeding disorders or reasonable suspicion of vascular malformations, for example, cerebral haemorrhage, 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 (INR), prothrombin time (PT), activated partial thromboplastin time (APTT) above the normal reference range or platelet count below the normal reference range at screening. * Positive fecal occult blood examination at screening. * Clinically significant abnormality in fundoscopic or petechiae examination. * Consumption of aspirin, other non-steroidal anti-inflammatory drugs or other drugs known to affect platelet function within 21 days prior to dosing. * Participants determined to be unsuitable by the investigator for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) | predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose | R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. |
| Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-tlast) | predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose | R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed AUC0-tlast was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect. |
| Pharmacokinetics of R-130964, Maximum Observed Drug Concentrations (Cmax) | predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose | R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed Cmax was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect. |
| Pharmacokinetics of R-130964, Time to Maximum Observed Drug Concentrations (Tmax) | predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose | R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Inhibition of Platelet Aggregation | predose and 2, 4, and 24 hours postdose | Blood samples for the measurement of platelet aggregation using a point-of-care device, Accumetrics VerifyNow™ P2Y12 (VN-P2Y12), were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Device-reported percent inhibition of VN-P2Y12 (IPRU) is presented. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clopidogrel First, Then LY2216684 + Clopidogrel Period 1: a single 300-milligram (mg) dose of clopidogrel administered orally on Day 1 (Treatment 1).
Period 2: an 18-mg dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).
There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2. | 24 |
| LY2216684 + Clopidogrel First, Then Clopidogrel Period 1: an 18-milligram (mg) dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).
Period 2: a single 300-mg dose of clopidogrel administered orally on Day 1 (Treatment 1).
There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2. | 23 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 | Adverse Event | 1 | 0 |
| Washout | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Clopidogrel First, Then LY2216684 + Clopidogrel | Total | LY2216684 + Clopidogrel First, Then Clopidogrel |
|---|---|---|---|
| Age, Continuous | 40.7 years STANDARD_DEVIATION 11.2 | 42.5 years STANDARD_DEVIATION 11.4 | 44.5 years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 28 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 19 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 5 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 | 20 Participants | 38 Participants | 18 Participants |
| Region of Enrollment United States | 24 Participants | 47 Participants | 23 Participants |
| Sex: Female, Male Female | 10 Participants | 22 Participants | 12 Participants |
| Sex: Female, Male Male | 14 Participants | 25 Participants | 11 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 | 12 / 47 | 19 / 46 | 11 / 45 |
| serious Total, serious adverse events | 0 / 47 | 0 / 46 | 0 / 45 |
Outcome results
Primary
Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞)
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
Time frame: predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Population: Participants with the CYP2C19\*1/\*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data, including sufficient data in the terminal elimination phase for R-130964.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) | 61.8 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 50 |
| LY2216684 + Clopidogrel | Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) | 55.3 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 44 |
Primary
Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-tlast)
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed AUC0-tlast was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
Time frame: predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Population: Participants with the CYP2C19\*1/\*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-tlast) | 60.5 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 45 |
| LY2216684 + Clopidogrel | Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-tlast) | 46.9 hours*nanograms/milliliters (h*ng/mL) | Geometric Coefficient of Variation 41 |
90% CI: [0.72, 0.83]Mixed Models Analysis
Primary
Pharmacokinetics of R-130964, Maximum Observed Drug Concentrations (Cmax)
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed Cmax was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
Time frame: predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Population: Participants with the CYP2C19\*1/\*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Clopidogrel | Pharmacokinetics of R-130964, Maximum Observed Drug Concentrations (Cmax) | 37.6 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 56 |
| LY2216684 + Clopidogrel | Pharmacokinetics of R-130964, Maximum Observed Drug Concentrations (Cmax) | 22.7 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
90% CI: [0.53, 0.67]Mixed Models Analysis
Primary
Pharmacokinetics of R-130964, Time to Maximum Observed Drug Concentrations (Tmax)
R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
Time frame: predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Population: Participants with the CYP2C19\*1/\*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clopidogrel | Pharmacokinetics of R-130964, Time to Maximum Observed Drug Concentrations (Tmax) | 1.50 hours |
| LY2216684 + Clopidogrel | Pharmacokinetics of R-130964, Time to Maximum Observed Drug Concentrations (Tmax) | 1.50 hours |
p-value: 0.330390% CI: [0, 0.25]Wilcoxon (Mann-Whitney)
Secondary
Percentage Inhibition of Platelet Aggregation
Blood samples for the measurement of platelet aggregation using a point-of-care device, Accumetrics VerifyNow™ P2Y12 (VN-P2Y12), were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Device-reported percent inhibition of VN-P2Y12 (IPRU) is presented.
Time frame: predose and 2, 4, and 24 hours postdose
Population: Participants with the CYP2C19\*1/\*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable IPRU data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Clopidogrel | Percentage Inhibition of Platelet Aggregation | Predose | 1.7 IPRU | Standard Deviation 3.2 |
| Clopidogrel | Percentage Inhibition of Platelet Aggregation | 2 Hours Postdose | 16.0 IPRU | Standard Deviation 20.3 |
| Clopidogrel | Percentage Inhibition of Platelet Aggregation | 4 Hours Postdose | 30.4 IPRU | Standard Deviation 21.8 |
| Clopidogrel | Percentage Inhibition of Platelet Aggregation | 24 Hours Postdose | 25.1 IPRU | Standard Deviation 21.1 |
| LY2216684 + Clopidogrel | Percentage Inhibition of Platelet Aggregation | 24 Hours Postdose | 14.3 IPRU | Standard Deviation 17.5 |
| LY2216684 + Clopidogrel | Percentage Inhibition of Platelet Aggregation | Predose | 1.4 IPRU | Standard Deviation 3.2 |
| LY2216684 + Clopidogrel | Percentage Inhibition of Platelet Aggregation | 4 Hours Postdose | 14.0 IPRU | Standard Deviation 16.6 |
| LY2216684 + Clopidogrel | Percentage Inhibition of Platelet Aggregation | 2 Hours Postdose | 7.6 IPRU | Standard Deviation 12.3 |