Disposition of Carbon-14-Labeled LY2886721 ([^14C]-LY2886721) Following Oral Administration in Healthy Human Participants

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01367262
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Days): 30
• Patients Per Site Per Month: 6.1

Study Details

Study Description

Brief Summary

This open-label study is being conducted to determine the metabolism and physiological disposition of radiolabeled LY2886721 after a single dose in healthy male participants.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: LY2886721	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Disposition of [14C]-LY2886721 Following Oral Administration in Healthy Human Subjects
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiolabeled LY2886721 Single 25 milligram (mg) oral dose containing 80 microCuries of radiolabeled LY2886721	Drug: LY2886721; Administered orally

Outcome Measures

Primary Outcome Measures

1. Percentage of Urinary and Fecal Excretion of LY2886721 Radioactivity Over Time [Predose up to 7 days (168 hours) postdose]

   Urinary and fecal excretion of LY2886721 radioactivity over time was expressed as a percentage of the total radioactive dose administered. The amount of drug-related material excreted in urine and feces (Ae) at a specific collection interval (i) was calculated as the product of radioactivity concentration and volume or weight. The Ae values for each collection interval were then summed and calculated as Total Ae=Ae(i1)+Ae(i2)+Ae(in). The percentage of the total radiolabeled dose administered that was excreted in feces or urine=[(Total Ae)/(Total radioactive dose administered)]*100.

Secondary Outcome Measures

1. Plasma Pharmacokinetics (PK) of LY2886721: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0 to Inf)] [Predose up to 4 days (96 hours) postdose]

2. PK of Radioactivity: AUC(0 to Inf) [Predose up to 4 days (96 hours) postdose]

   AUC(0 to inf) for plasma and whole blood total radioactivity is reported as hours*nanogram equivalents per milliliter (h*ng Eq/mL).

3. Plasma PK of LY2886721: Maximum Observed Concentration (Cmax) [Predose up to 4 days (96 hours) postdose]

4. PK of Radioactivity: Cmax [Predose up to 4 days (96 hours) postdose]

   The Cmax of total radioactivity in plasma and whole blood are reported as nanogram equivalents per milliliter (ng Eq/mL).

5. Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Plasma [1 to 8 hours postdose]

   The metabolites of LY2886721 were identified using a high performance liquid chromatography (HPLC) chromatogram. The relative abundance of LY2886721 and its metabolites in plasma were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.

6. Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Urine [0 to 72 hours postdose]

   The metabolites of LY2886721 were identified using an HPLC chromatogram. The relative abundance of LY2886721 and its metabolites in urine were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.

7. Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Feces [0 to 144 hours postdose]

   The metabolites of LY2886721 were identified using an HPLC chromatogram. The relative abundance of LY2886721 and its metabolites in feces were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy males as determined by medical history and physical examination

• Males will be sterile (including vasectomy) or if the participant is not sterile and is sexually active, he will agree to use from check-in until 3 months after exit/discharge, 1 of the following approved methods of contraception: a male condom with spermicide, a sterile sexual partner, use by female sexual partner of an intrauterine device with spermicide, a female condom with spermicide, contraceptive sponge with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, or oral, implantable, transdermal, intravaginal, or injectable contraceptives

• Have a body mass index of 19 to 30 kilograms per square meter (kg/m^2)

• 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

• Have normal blood pressure and heart rate (sitting)

• Experience a minimum of at least 1 bowel movement per day

• 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 other than the investigational product used in this study; 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 LY2886721, 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 LY2886721

• Have a Bazett's corrected QT (QTcB) interval value of >450 milliseconds (msec) or any abnormality in the 12-lead electrocardiogram (ECG) increases the risks associated with participating in the study

• Have an abnormal blood pressure

• 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 (HIV) infection and/or positive 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

• Intend to use prescription medication, over-the-counter medication, or herbal preparations containing St. John's Wort, kava, garlic, ginger, ginko biloba, or guarana within 14 days prior to admission

• Eating of grapefruit or grapefruit-containing foods, or drinking grapefruit-containing juices within 7 days prior to dosing or any time during the study

• Have used any tobacco- 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 dosing

• Have donated blood of more than 500 milliliters (mL) within the last month

• Have an average weekly alcohol intake that exceeds 21 units per week (males up to age 65), or are unwilling to stop alcohol consumption from 48 hours prior to check-in until end of 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]

• Show evidence of significant active neuropsychiatric disease, in particular evidence of significant medical or psychiatric illness within the past 12 months. Have any other condition that would preclude participation in the study

• Have a history or presence of epilepsy, a history of seizures, any known brain abnormalities, and a history of significant brain injury

• Have participated in a [^14C] study within the last 6 months prior to check-in for this study. The total exposure from this study and the previous study must be within the Code of Federal Regulations (CFR) recommended levels considered safe (per 21 CFR 361.1), less than 5,000 millirems (mrem)/year whole body annual exposure

• Exposure to significant radiation within 12 months prior to dose (for example, serial X-ray or computed tomography scans, barium meal, current employment in a job requiring radiation exposure monitoring)

• Have a history of clinically significant adverse drug reactions or "drug allergy" to more than 3 types of systemically administered medications (all penicillins and cephalosporins may be considered 1 type of medication for this purpose)

• Have a history of, or current, significant ophthalmological disease

• Have evidence of active renal disease (for example, diabetic renal disease, polycystic kidney disease) or creatinine clearance of <80 milliliters per minute (mL/min) as calculated by Cockcroft-Gault equation: Men: (140-age)weight in kilograms (kg)/72[serum creatinine in milligrams per deciliter (mg/dL)]

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Madison	Wisconsin	United States

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 am - 5 pm Eastern Time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01367262
• Other Study ID Numbers: 13736; I4O-MC-BACD
• First Posted: Jun 7, 2011
• Last Update Posted: Sep 13, 2019
• Last Verified: May 1, 2019

• Keywords provided by Eli Lilly and Company: Absorption; Distribution; Metabolism; Excretion

Study Results

Participant Flow

Pre-assignment Detail	Participants were considered to have completed the study at 9 days postdose or earlier if ≥90% of administered radioactivity recovered or 24-hour urine and fecal samples from 2 consecutive collections each had radioactivity levels <1.0% of total administered radioactivity in urine and feces combined.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-milligram (mg) LY2886721 dose containing approximately 80 microCuries (μCi) of carbon-14-labeled LY2886721 ([^14C]-LY2886721), administered as an oral solution.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Overall Participants	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.2 (12.4)
Sex/Gender, Customized (Count of Participants)
Males	6 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%
Not Hispanic or Latino	5 83.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 16.7%
White	5 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Urinary and Fecal Excretion of LY2886721 Radioactivity Over Time
Description	Urinary and fecal excretion of LY2886721 radioactivity over time was expressed as a percentage of the total radioactive dose administered. The amount of drug-related material excreted in urine and feces (Ae) at a specific collection interval (i) was calculated as the product of radioactivity concentration and volume or weight. The Ae values for each collection interval were then summed and calculated as Total Ae=Ae(i1)+Ae(i2)+Ae(in). The percentage of the total radiolabeled dose administered that was excreted in feces or urine=[(Total Ae)/(Total radioactive dose administered)]*100.
Time Frame	Predose up to 7 days (168 hours) postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
Urine	85.7 (2.44)
Feces	8.86 (0.868)

2. Secondary Outcome

Title	Plasma Pharmacokinetics (PK) of LY2886721: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0 to Inf)]
Time Frame	Predose up to 4 days (96 hours) postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
Geometric Mean (Geometric Coefficient of Variation) [hours*nanograms per milliliter (h*ng/mL)]	681 (13)

3. Secondary Outcome

Title	PK of Radioactivity: AUC(0 to Inf)
Description	AUC(0 to inf) for plasma and whole blood total radioactivity is reported as hours*nanogram equivalents per milliliter (h*ng Eq/mL).
Time Frame	Predose up to 4 days (96 hours) postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
Plasma Total Radioactivity	3310 (13)
Whole Blood Total Radioactivity	2470 (13)

4. Secondary Outcome

Title	Plasma PK of LY2886721: Maximum Observed Concentration (Cmax)
Time Frame	Predose up to 4 days (96 hours) postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)]	56.3 (15)

5. Secondary Outcome

Title	PK of Radioactivity: Cmax
Description	The Cmax of total radioactivity in plasma and whole blood are reported as nanogram equivalents per milliliter (ng Eq/mL).
Time Frame	Predose up to 4 days (96 hours) postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
Plasma Total Radioactivity	218 (15)
Whole Blood Total Radioactivity	165 (16)

6. Secondary Outcome

Title	Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Plasma
Description	The metabolites of LY2886721 were identified using a high performance liquid chromatography (HPLC) chromatogram. The relative abundance of LY2886721 and its metabolites in plasma were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.
Time Frame	1 to 8 hours postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
LY2886721 (parent) 1-hour(h) Postdose	42.1 (9.8)
Predominant Metabolite 1h Postdose	18.0 (6.6)
LY2886721 (parent) 2h Postdose	38.3 (6.4)
Predominant Metabolite 2h Postdose	15.7 (6.5)
LY2886721 (parent) 4h Postdose	37.2 (6.6)
Predominant Metabolite 4h Postdose	13.7 (3.1)
LY2886721 (parent) 8h Postdose	39.4 (12.9)
Predominant Metabolite 8h Postdose	15.2 (2.8)

7. Secondary Outcome

Title	Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Urine
Description	The metabolites of LY2886721 were identified using an HPLC chromatogram. The relative abundance of LY2886721 and its metabolites in urine were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.
Time Frame	0 to 72 hours postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
LY2886721 (parent)	12.3 (3.7)
Predominant Metabolite	36.4 (3.6)

8. Secondary Outcome

Title	Relative Abundance of LY2886721 and the Metabolites of LY2886721 in Feces
Description	The metabolites of LY2886721 were identified using an HPLC chromatogram. The relative abundance of LY2886721 and its metabolites in feces were reported as a percentage of recovered radioactivity and calculated by dividing the sum of the radioactive content of fractions contributing to a particular peak by the sum of the radioactive content of all fractions in the radio chromatogram, then multiplying by 100. Radioactivity corresponds to 80 μCi [^14C]-LY2886721.
Time Frame	0 to 144 hours postdose

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
Measure Participants	6
LY2886721 (parent)	NA (NA)
Metabolites	4.1 (2.4)

Adverse Events

Arm/Group Title	[^14C]-LY2886721
Arm/Group Description	Single 25-mg LY2886721 dose containing approximately 80 μCi of [^14C]-LY2886721, administered as an oral solution.
All Cause Mortality
	[^14C]-LY2886721
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	[^14C]-LY2886721
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	[^14C]-LY2886721
	Affected / at Risk (%)	# Events
Total	3/6 (50%)
General disorders
Application site erythema	2/6 (33.3%)	2
Vessel puncture site haematoma	1/6 (16.7%)	1
Nervous system disorders
Headache	1/6 (16.7%)	2

Limitations/Caveats

Assay sensitivity of plasma and whole blood radioactivity were not generally quantifiable after 24-hours postdose. Consequently, the AUC(0-inf) estimate for total radioactivity in plasma and whole blood should be considered underestimated.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.