Healthy Participants
Conditions
Keywords
Low High-density Lipoprotein (HDL), Cholesterol (HDL-C)
Brief summary
This is a 2-part study. Part 1 is to determine the safety and tolerability in healthy participants of increasing daily doses of LY2484595 for 14 days to achieve a blood level of LY2484595 much higher than what is needed for therapy. The amount of study drug that reaches the bloodstream and the time it takes for the body to get rid of it will be determined. The effect of the study drug on factors in the blood related to cholesterol will be measured. Part 2 is to determine how ketoconazole affects how much of the study drug, LY2484595, gets into the bloodstream and how long it takes to get rid of it. Information about any side effects that may occur will also be collected.
Detailed description
This study is a 2-part, multiple ascending dose (MAD) and drug drug interaction (DDI) study to evaluate the safety and tolerability and the effect of cytochrome P450 (CYP) 3A inhibition by ketoconazole on the pharmacokinetics of LY2484595 in healthy participants. In the MAD portion (Part 1) of this study, participants in 4 cohorts (Cohorts A through D) will be randomized to receive either LY2484595 (5 ascending dose levels \[100 to 1800 mg\]) or placebo. Cohorts will have staggered starts ≥7 days from the previous cohort to allow for review of safety and tolerability. The total duration of Part 1 is approximately 13 weeks including screening. Participants in Cohort A will participate in 2 periods separated by a washout period lasting ≥14 days. During Period 1, participants will receive the starting dose of LY2484595 (100 mg) or placebo once daily (QD) for 14 consecutive days. During Period 2, participants will receive the highest dose of LY2484595 (1800 mg) or placebo QD for 14 consecutive days. Participants will complete a follow-up visit ≥14 days after the last dose of study drug. Participants in Cohorts B, C, and D will receive LY2484595 (300, 600, and 1200 mg LY2484595, respectively) or placebo QD for 14 consecutive days followed by a follow-up visit ≥14 days after last dose of study drug. The DDI portion of this study (Part 2) will be open label and consist of 2 periods. The total duration of Part 2 is approximately 10 weeks. LY2484595 (100 mg) will be administered on Day 1 of Period 1 and on Day 5 of Period 2. In Period 2, ketoconazole (400 mg) will be administered QD for 14 consecutive days (13 days alone \[Days 1 through 4 and 6 through 14\] + 1 day with LY2484595 \[Day 5\]). There will be a ≥14-day washout period between dosing during Period 1 and Period 2. Participants will return for a follow-up visit ≥14 days after last dose of study drug.
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Are overtly healthy males or females, as determined by medical history and physical examination * Female participants and women not of childbearing potential due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) or menopause. Postmenopausal is defined as women age \>45 with an intact uterus who have not taken hormones or oral contraceptives within the last year, and who have had either cessation of menses greater than or equal to 1 year or 6 to 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) \>40 milli-international units per milliliter (40 international units per liter \[IU/L\]). * Have a body mass index (BMI) between 18 to 32 kilograms per square meter (kg/m\^2), inclusive * 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 * 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
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 to LY2484595 or related compounds, contraindications to ketoconazole or related compounds, or allergies to any components of the formulations * Are persons who have previously completed or withdrawn from this study or any other study investigating LY2484595 and have previously received the investigational product * 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 and/or poses difficulties in the interpretation of eventual changes occurring during the study * Have systolic blood pressure of \>140 millimeters of mercury (mmHg) or diastolic blood pressure of \>90 mmHg * Have a history or presence of 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 * Regularly use known drugs of abuse and/or show positive findings on urinary drug screening * Show evidence of human immunodeficiency virus infection (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 * Have used or 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 * Use of any drugs or substances that are known to be an inducer or inhibitor of cytochrome p450 3A4 (CYP3A4) (for example, St. John's wort) within 30 days prior to first dose of study drug * Have donated blood of more than 500 milliliters (mL) within 30 days prior to first dose of study drug * 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 for the duration of the study (1 unit equals 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 restriction * Have a daily use of greater than or equal to 5 tobacco- or nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) and are unwilling to refrain from using any tobacco- or nicotine-containing products within 7 days prior to first dose through the follow-up visit * Have consumed grapefruit, grapefruit juice, Seville orange, Seville orange juice, or starfruit or products that contain these fruits within 7 days prior to first dose and during the study * Unwilling to refrain from daily consumption of black licorice containing glycyrrhizic acid (that is, real licorice) * In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Part 1: Baseline through ≥14 days after last dose of study drug (≥Day 28) | The number of participants with 1 or more AEs is summarized cumulatively. In addition, the number of participants with any serious AEs is summarized cumulatively. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. |
| Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | The geometric least squares (LS) means for the maximum observed plasma concentration (Cmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone). |
| Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | The median times to maximum observed plasma concentration (Tmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. |
| Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | The geometric least squares (LS) means of area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC0-∞) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | Day 1 (Baseline) and Day 21 | — |
| Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | Day 1 (Baseline) and Day 21 | — |
| Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | The maximum observed plasma concentrations (Cmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. |
| Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | The times of maximum observed plasma concentrations (tmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. |
| Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | Exposure to LY2484595 in terms of the area under the concentration-time curves (AUC) after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. |
Countries
United States
Participant flow
Pre-assignment details
This was a 2-part study, multiple ascending dose (MAD) and drug drug interaction (DDI). Participants were randomized to (Part 1) to 4 cohorts (Cohorts A through D) and randomized to receive either LY2484595 (5 ascending dose levels) or placebo. Cohort A consisted of 2 periods separated by a washout period of 14 days. DDI had 2 periods.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 (Cohort A) Sequence 1 Participants received 100 milligrams (mg) LY2484595 (tablets, oral administration) QD on Days 1 through 14. Then, received 1800 mg LY2484595 QD on Days 1 through 14 period 2. | 12 |
| Part 1 (Cohort A) Sequence 2 Placebo: tablets, oral administration, once daily (QD) on Days 1 through 14 of Period 1 and 1800 mg LY2484595 on Days 1 through 14 of Period 2). | 4 |
| Part 1 (Cohort A) Sequence 3 Participants received 100 mg LY2484595 (tablets, oral administration) once daily (QD) on Days 1 through 14. Then, received placebo QD on Days 1 through 14 period 2. | 4 |
| Part 1 (Cohort B Through D) Placebo Placebo: tablets, oral administration, once daily (QD) on Days 1 through 14. | 10 |
| Part 1 (Cohort B) Participants received 300 mg LY2484595 (tablets, oral administration) QD on Days 1 through 14. | 16 |
| Part 1 (Cohort C) Participants received 600 mg LY2484595 (tablets, oral administration) QD on Days 1 through 14. | 12 |
| Part 1 (Cohort D) Participants received 1200 mg LY2484595 (tablets, oral administration) QD on Days 1 through 14. | 12 |
| Part 2 (Cohort E) Participants received 100 mg LY2484595 (tablet, oral administration) as a single dose on Day 1 of Period 1. After a washout period lasting ≥14 days, participants received 400 mg ketoconazole (tablet, oral administration, QD) on Days 1 through 4 of Period 2, 400 mg ketoconazole (tablet, oral administration) and 100 mg LY2484595 (tablet, oral administration) on Day 5 of Period 2, and 400 mg ketoconazole (tablet, oral administration, QD) on Days 6 through 14 of Period 2. | 12 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Part 1 Period 1: Multiple Ascending Dose | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 1 Period 1: Multiple Ascending Dose | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 1 Period 1: Multiple Ascending Dose | Withdrawal by Subject | 0 | 0 | 0 | 1 | 2 | 1 | 0 | 0 |
| Part 1: Washout Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 2 Period 1: Drug-drug Interaction | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 Period 2: Drug-drug Interaction | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 Period 2: Drug-drug Interaction | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 Period 2: Drug-drug Interaction | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 2 (Cohort E) | Part 1 (Cohort A) Sequence 1 | Part 1 (Cohort A) Sequence 2 | Part 1 (Cohort A) Sequence 3 | Part 1 (Cohort B Through D) Placebo | Total | Part 1 (Cohort B) | Part 1 (Cohort C) | Part 1 (Cohort D) |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.6 years STANDARD_DEVIATION 7.9 | 38.4 years STANDARD_DEVIATION 11.6 | 31.3 years STANDARD_DEVIATION 3.9 | 41.8 years STANDARD_DEVIATION 7.4 | 39.4 years STANDARD_DEVIATION 13.7 | 39.8 years STANDARD_DEVIATION 11.5 | 41.1 years STANDARD_DEVIATION 14.3 | 39.1 years STANDARD_DEVIATION 10.7 | 45.8 years STANDARD_DEVIATION 11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 1 Participants | 3 Participants | 4 Participants | 41 Participants | 6 Participants | 8 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 3 Participants | 1 Participants | 6 Participants | 41 Participants | 10 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 21 Participants | 5 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 6 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 9 Participants | 2 Participants | 3 Participants | 7 Participants | 53 Participants | 9 Participants | 10 Participants | 8 Participants |
| Region of Enrollment United States | 12 Participants | 12 Participants | 4 Participants | 4 Participants | 10 Participants | 82 Participants | 16 Participants | 12 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 3 Participants | 19 Participants | 5 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 3 Participants | 4 Participants | 7 Participants | 63 Participants | 11 Participants | 10 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 18 | 2 / 16 | 11 / 15 | 4 / 16 | 2 / 12 | 6 / 12 | 4 / 12 | 5 / 11 | 2 / 10 |
| serious Total, serious adverse events | 0 / 18 | 0 / 16 | 0 / 15 | 0 / 16 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 10 |
Outcome results
Primary
Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs
The number of participants with 1 or more AEs is summarized cumulatively. In addition, the number of participants with any serious AEs is summarized cumulatively. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Part 1: Baseline through ≥14 days after last dose of study drug (≥Day 28)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 7 Participants |
| Part 1 (Cohorts A Through D): Placebo | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 2 Participants |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1 (Cohort B): 300 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 4 Participants |
| Part 1 (Cohort B): 300 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1 (Cohort C): 600 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1 (Cohort C): 600 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 2 Participants |
| Part 1 (Cohort D): 1200 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 6 Participants |
| Part 1 (Cohort D): 1200 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1, Period 2 (Cohort A): 1800 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | Serious AEs | 0 Participants |
| Part 1, Period 2 (Cohort A): 1800 mg LY2484595 | Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | AEs | 11 Participants |
Primary
Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595
The geometric least squares (LS) means of area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC0-∞) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone).
Time frame: Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose
Population: Participants who received at least 1 dose of LY2484595 and had at least 3 consecutive plasma LY2484595 concentrations above the lower limit of quantification with at least 1 of these concentrations following the maximum observed plasma concentration (Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | 5265 Nanograms * hours per milliliter |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | 12471 Nanograms * hours per milliliter |
90% CI: [1.77, 3.18]
Primary
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595
The geometric least squares (LS) means for the maximum observed plasma concentration (Cmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone).
Time frame: Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose
Population: Participants who received at least 1 dose of LY2484595 and had evaluable LY2484595 concentration data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | 331.83 Nanograms per milliliter (ng/mL) |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | 643.99 Nanograms per milliliter (ng/mL) |
90% CI: [1.39, 2.72]
Primary
Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595
The median times to maximum observed plasma concentration (Tmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported.
Time frame: Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose
Population: Participants who received at least 1 dose of LY2484595 and had evaluable LY2484595 concentration data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | 3.00 Hours (h) |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | 3.00 Hours (h) |
p-value: 190% CI: [-0.5, 0.5]Wilcoxon signed rank
Secondary
Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity
Time frame: Day 1 (Baseline) and Day 21
Population: Participants who received at least 1 dose of LY2484595 or placebo and had evaluable pharmacodynamic (CETP) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | 1.3 Picomoles per milliliters per minute | Standard Deviation 6.9 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | -0.4 Picomoles per milliliters per minute | Standard Deviation 3.1 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | -0.4 Picomoles per milliliters per minute | Standard Deviation 6.3 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | -9.1 Picomoles per milliliters per minute | Standard Deviation 8.8 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | -9.5 Picomoles per milliliters per minute | Standard Deviation 5 |
| Part 1, Period 2 (Cohort A): 1800 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity | -12.9 Picomoles per milliliters per minute | Standard Deviation 7.5 |
Secondary
Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG)
Time frame: Day 1 (Baseline) and Day 21
Population: Participants who received at least 1 dose of LY2484595 or placebo during Period 1 and had evaluable pharmacodynamic (HDL-C, LDL-C, TG) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | LDL-C | -0.42 Millimoles per liter (mmol/L) | Standard Deviation 0.74 |
| Part 1 (Cohorts A Through D): Placebo | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | HDL-C | -0.08 Millimoles per liter (mmol/L) | Standard Deviation 0.17 |
| Part 1 (Cohorts A Through D): Placebo | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | TG | 0.56 Millimoles per liter (mmol/L) | Standard Deviation 0.87 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | HDL-C | 0.35 Millimoles per liter (mmol/L) | Standard Deviation 0.22 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | LDL-C | -0.16 Millimoles per liter (mmol/L) | Standard Deviation 0.31 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | TG | 0.55 Millimoles per liter (mmol/L) | Standard Deviation 0.81 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | HDL-C | 0.49 Millimoles per liter (mmol/L) | Standard Deviation 0.31 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | TG | 0.44 Millimoles per liter (mmol/L) | Standard Deviation 0.61 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | LDL-C | -0.48 Millimoles per liter (mmol/L) | Standard Deviation 0.55 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | HDL-C | 0.77 Millimoles per liter (mmol/L) | Standard Deviation 0.49 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | LDL-C | -1.15 Millimoles per liter (mmol/L) | Standard Deviation 0.93 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | TG | 0.26 Millimoles per liter (mmol/L) | Standard Deviation 0.38 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | LDL-C | -1.01 Millimoles per liter (mmol/L) | Standard Deviation 0.57 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | HDL-C | 0.80 Millimoles per liter (mmol/L) | Standard Deviation 0.22 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) | TG | 0.52 Millimoles per liter (mmol/L) | Standard Deviation 0.57 |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595
Exposure to LY2484595 in terms of the area under the concentration-time curves (AUC) after a single dose and after once daily (QD) dosing for 14 consecutive days are reported.
Time frame: Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose
Population: All participants who received at least 1 dose of LY2484595 and had at least 3 consecutive plasma LY2484595 concentrations above the lower limit of quantification with at least 1 of these concentrations following the maximum observed plasma concentration (Cmax).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 1 | 4780 Nanograms * hour per milliliter | Geometric Coefficient of Variation 57 |
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 14 | 8110 Nanograms * hour per milliliter | Geometric Coefficient of Variation 30 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 1 | 14500 Nanograms * hour per milliliter | Geometric Coefficient of Variation 47 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 14 | 17900 Nanograms * hour per milliliter | Geometric Coefficient of Variation 27 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 1 | 21300 Nanograms * hour per milliliter | Geometric Coefficient of Variation 55 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 14 | 36200 Nanograms * hour per milliliter | Geometric Coefficient of Variation 38 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 14 | 46900 Nanograms * hour per milliliter | Geometric Coefficient of Variation 43 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 1 | 36300 Nanograms * hour per milliliter | Geometric Coefficient of Variation 46 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 1 | 31300 Nanograms * hour per milliliter | Geometric Coefficient of Variation 63 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Day 14 | 56600 Nanograms * hour per milliliter | Geometric Coefficient of Variation 30 |
Secondary
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595
The maximum observed plasma concentrations (Cmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported.
Time frame: Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose
Population: Participants who received at least 1 dose of LY2484595 and had evaluable LY2484595 concentration data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 1 | 628 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 79 |
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 14 | 978 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 1 | 1990 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 60 |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 14 | 1970 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 1 | 2720 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 59 |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 14 | 4180 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 14 | 5410 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 48 |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 1 | 4450 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 1 | 3580 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 73 |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | Day 14 | 5750 Nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
Secondary
Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595
The times of maximum observed plasma concentrations (tmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported.
Time frame: Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose
Population: Participants who received at least 1 dose of study drug and had evaluable LY2484595 concentration data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 14 | 4.00 Hours (h) |
| Part 1 (Cohorts A Through D): Placebo | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 1 | 3.00 Hours (h) |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 1 | 3.00 Hours (h) |
| Part 1, Period 1 (Cohort A): 100 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 14 | 2.00 Hours (h) |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 1 | 3.00 Hours (h) |
| Part 1 (Cohort B): 300 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 14 | 2.50 Hours (h) |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 1 | 2.00 Hours (h) |
| Part 1 (Cohort C): 600 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 14 | 2.00 Hours (h) |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 14 | 3.00 Hours (h) |
| Part 1 (Cohort D): 1200 mg LY2484595 | Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | Day 1 | 2.00 Hours (h) |