The purpose of this study is to evaluate the effects of diltiazem on the pharmacokinetics (PK) and pharmacodynamics (PD) of E5555 and its metabolites in healthy subjects.

This is an open-label, 2-arm study to evaluate the effects of diltiazem given in conjunction with E5555 on the PK of diltiazem and its metabolites. This is a Phase 1 study of 24 healthy male and female subjects that will be conducted at a single site. The planned duration of treatment for each subject is approximately 15 days including 1 day in Treatment Period 1 and 14 days in Treatment Period 2.

Inclusion:

• Provide written informed consent
• Healthy, non-smoking, male or female subjects aged greater than or equal to 18 years to 55 years
• Body mass index (BMI) greater than or equal to 18 and less than or equal to 32 kg/m2 at Screening
• All females must have a negative serum beta human chorionic gonadotropin test result at Screening and Baseline. Females of child-bearing potential must agree to use a medically acceptable method of contraception commencing at least one menstrual cycle prior to starting study drug, throughout the entire study period and for 90 days after study drug discontinuation. The only subjects who will be exempt from this requirement are postmenopausal women or subjects who have been surgically sterilized or who are otherwise proven sterile.
• Male subjects who are partners of women of childbearing potential and are not abstinent or have not undergone a successful vasectomy must use, or their partners must use, a highly effective method of contraception commencing at least one menstrual cycle prior to starting study drug, throughout the entire study period and for 90 days after study drug discontinuation.
• Are willing and able to comply with all aspects of the protocol.

Exclusion:

• A family history, past medical history or clinical signs or symptoms of a bleeding diathesis
• History of any medical condition which will result in an increased risk of bleeding including but not limited to active or recurrent gastric ulcers, recent head trauma or surgery, severe hypertension, bacterial endocarditis etc
• Subjects with a history of spontaneous gum bleeding or clinical signs or symptoms on physical exam
• Clinically significant ocular disease or untreated visual or ocular symptoms
• Clinically significant abnormal electrocardiograms ECGs prior to dosing (Screening or Baselines) including a QT interval corrected for heart rate using Fredericia's formula (QTcF) and/or Bazett's formula (QTcB) greater than 450 ms
• Any history or past medical condition that will result in QTc prolongation or tachyarrhythmia such as Torsades de Points (includes hypokalemia, known family history of long QT syndrome, or any other known risk factors for Torsades de Points)
• A platelet count less than 150,000 or greater than 390,000 per mL at Screening or Baseline Period 1
• Abnormal (less than 80%) arachidonic acid induced platelet aggregation at Baseline Period 1
• History of unexplained syncope, hepato-bliary disease, sinus bradycardia, heart blocks, sick-sinus syndrome, cardiogenic shock, heart failure, seizures, or chronic obstructive lung disease
• Subjects with hypotension (less than 90 mm Hg systolic) and bradycardia (HR less than 40 beats per minute) or symptomatic bradycardia (HR less than 50 beats per minute)
• Received blood, donated blood, or experienced significant blood loss within 60 days prior to check-in
• Hypersensitivity to diltiazem or related compounds or ingredients in the formulation