A Pharmacokinetic Study on the Effect of LY2216684 on the Active Metabolite of Clopidogrel

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.

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.