Depressive Disorder, Major
Conditions
Brief summary
The study will evaluate the effect of Clarithromycin on the pharmacokinetics (PK) of LY2216684 in healthy participants. Side effects will be documented. There will be 2 study periods (5 and 9 days) and follow up will occur at least 7 days after the last dose. Screening is required within 45 days prior to the start of the study.
Interventions
DRUGLY2216684
Administered orally
DRUGClarithromycin
Administered orally
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: o 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: o Are women of child-bearing potential who test negative for pregnancy at the time of enrollment, have used a reliable method of birth control (not including hormonal contraceptives) for 4 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, bilateral oophorectomy, or tubal ligation/occlusion) 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 for blood sampling as per the protocol * 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 institutional review board (IRB) governing the site * Have normal blood pressure (BP) and pulse rate (PR) (sitting position) as determined by the investigator * Are predicted to have both cytochrome P450 (CYP)2D6 and CYP2C19 extensive metabolizer (EM) phenotypes as determined by genotyping assessment
Exclusion criteria
* Are currently enrolled in, have completed or discontinued within the last 30 days from a clinical trial involving an investigational product 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/intolerance to LY2216684 or clarithromycin, related compounds, or any components of the formulation * Are persons who have previously received the investigational product in this study, have 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 * Have a documented or suspected history of glaucoma * Regularly use known drugs of abuse and/or show positive findings on urinary drug screening * Show evidence of human immunodeficiency virus (HIV) infection 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. Exceptions include influenza vaccinations, the use of topical medication (provided there is no evidence of chronic dosing with the risk of systemic exposure), occasional use of acetaminophen/paracetamol/ibuprofen, hormone replacement therapy including thyroid replacement (stable dose for at least 1 month) * Use of known inhibitors and/or inducers of CY2D6, CYP2C19, and/or CYP3A 30 days prior to enrollment or are unwilling to avoid them during the study (except for use of clarithromycin) * Have donated blood of more than 500 mL within the last month * Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females), or are unwilling to stop alcohol consumption 48 hours prior to dosing in Period 1 until discharge \[1 unit = 12 oz (ounces) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits\] * Consume 5 or more cups of coffee (or other beverages or foods of comparable caffeine content) per day, on a habitual basis, or are unwilling to stop caffeine consumption from 48 hours prior to dosing in Period 1 until discharge * Participants unwilling to adhere to the smoking restrictions of the Clinical Research Unit (CRU) while a resident of the CRU * Have consumed grapefruit or grapefruit-containing products, starfruit, or pomegranates 30 days prior to enrollment or are unwilling to avoid them during the study * Participants 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 to Infinity (AUC0-∞) of LY2216684 | Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10) | AUC0-∞ of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric Least Squares (LS) mean and the 90% Confidence Interval (CI). Geometric LS mean was controlled by participant and treatment. |
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of LY2216684 | Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10) | Cmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment. |
| Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10) | Tmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population LY2216684: a single 18-mg tablet on Day 1 and Day 10
Clarithromycin: 500-mg tablet twice daily on Day 6 through Day 13 | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2: Day 6 to Day 14 | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 43.5 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 12 Participants |
| Region of Enrollment United States | 14 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 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 | 6 / 14 | 6 / 14 | 4 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-∞) of LY2216684
AUC0-∞ of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric Least Squares (LS) mean and the 90% Confidence Interval (CI). Geometric LS mean was controlled by participant and treatment.
Time frame: Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10)
Population: Full Analysis Set: Participants who received at least 1 dose of LY2216684.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LY2216684 | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-∞) of LY2216684 | 582 nanogram*hours per milliliter (ng*h/mL) |
| LY2216684 and Clarithromycin | Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-∞) of LY2216684 | 746 nanogram*hours per milliliter (ng*h/mL) |
90% CI: [1.16, 1.42]
Primary
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of LY2216684
Cmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment.
Time frame: Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10)
Population: Full Analysis Set: Participants who received at least 1 dose of LY2216684.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LY2216684 | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of LY2216684 | 52.58 nanograms per milliliter (ng/mL) |
| LY2216684 and Clarithromycin | Pharmacokinetics: Maximum Plasma Concentration (Cmax) of LY2216684 | 63.55 nanograms per milliliter (ng/mL) |
90% CI: [1.12, 1.31]
Primary
Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of LY2216684
Tmax of LY2216684 was calculated during Period 1, when 18-mg LY2216684 was administered alone, and Period 2, when Clarithromycin was coadministered with LY2216684. The outcome was presented as geometric LS mean and the 90% CI. Geometric LS mean was controlled by participant and treatment.
Time frame: Predose up to 96 hours post administration of LY2216684 (Day 1) and LY2216684 + Clarithromycin (Day 10)
Population: Full Analysis Set: Participants who received at least 1 dose of LY2216684.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY2216684 | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | 2.00 hours (h) |
| LY2216684 and Clarithromycin | Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of LY2216684 | 2.00 hours (h) |
p-value: 0.765690% CI: [-0.5, 0.5]Wilcoxon (Mann-Whitney)