Absorption, Metabolism and Excretion of [14C]-Lasmiditan - Single Oral Dose Administration

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03040362
• Collaborator: CoLucid Pharmaceuticals (Industry)
• Enrollment: 8
• Location: 1
• Arm: 1
• Actual Duration (Days): 16
• Patients Per Site Per Month: 15.2

Study Details

Study Description

Brief Summary

This study will be an open-label, nonrandomized, absorption, metabolism, and excretion study of [14C]-lasmiditan administered as a 200-milligrams (mg) (approximately 100 microcuries[µCi]) oral solution to 8 healthy males and females, following at least a 10 hour fast from food to assess the pharmacokinetics (PK), metabolism, and routes and extent of elimination of a single oral dose of 200 mg (approximately 100 µCi) [14C] lasmiditan in healthy males and females.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: [14C]-lasmiditan	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 1 Study to Investigate the Absorption, Metabolism, and Excretion of [14C]-Lasmiditan Following Single Oral Dose Administration in Healthy Male and Female Subjects
• Actual Study Start Date: Apr 20, 2017
• Actual Primary Completion Date: May 6, 2017
• Actual Study Completion Date: May 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: [14C]-lasmiditan [14C]-lasmiditan administered as a 200 mg (approximately 100 µCi) oral solution	Drug: [14C]-lasmiditan; [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution; Other Names: LY573144

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) [Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose]

   Maximum observed concentration based on plasma concentrations of lasmiditan.

2. Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) [Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours pos-tdose]

   Time to maximum concentration based on plasma concentrations of lasmiditan.

3. Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to Tlast (AUC[0-tlast]) [Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose]

   Area under concentration time curve (AUC) from Hour 0 to the last measurable concentration based on plasma concentrations of lasmiditan.

4. AUC Time Zero to Infinity (AUC0-∞) Blood/Plasma Ratio [Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose]

   AUC time zero to infinity (0-∞) of total radioactivity in blood/AUC0-∞ of total radioactivity in plasma.

5. AUC Time Zero to Infinity (AUC0-∞) Plasma Lasmiditan/Total Radioactivity Ratio [Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours pos-tdose]

   AUC time zero to infinity (0-∞) of lasmiditan in plasma/AUC0-∞ of total radioactivity in plasma.

Secondary Outcome Measures

1. Pharmacokinetics - Cumulative Amount of Lasmiditan and Its Metabolites Excreted in Urine [Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose]

   Amount of Lasmiditan and its metabolites (M3, M7, M8, (S,R)-M18, and (S,S)-M18) excreted in urine (Aeu) over sampling interval.

2. Percentage of Lasmiditan Recovered in Urine, Relative to Dose Administered [Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose]

   Percentage of lasmiditan recovered in urine (%UR), relative to dose administered calculated as %UR = 100 (amount of lasmiditan excreted in urine over a sampling interval (Aeu)/dose).

3. Renal Clearance (CLR) [Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose]

   Renal clearance is the volume of plasma completely cleared of lasmiditan by the kidneys per unit time and calculated as CLR = Aeu/AUC0-x (where Aeu = amount of lasmiditan excreted in urine over a sampling interval; x is the last interval collected; for lasmiditan only).

4. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 49 days]

   Safety assessed from time of consent through end of study (up to 49 days). A summary of all reported serious adverse events (SAE) and other adverse events regardless of causality are provided in the Adverse Events module of this record.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Males and females, between 18 and 60 years of age, inclusive, at Screening

• Have a body mass index range of 18.5 to 32.0 kilograms per meter squared (kg/m²), inclusive, at Screening

• In good health, determined by no clinically significant findings from medical history, 12 lead electrocardiogram (ECG), and vital signs measurements at Screening or Check-in (Day 1) as determined by the Investigator (or designee)

• Clinical laboratory evaluations (including clinical chemistry panel [fasted at least 10 hours], hematology/complete blood count [CBC], and urinalysis [UA]; within the reference range for the test laboratory at Screening and Check-in, unless deemed not clinically significant by the Investigator (or designee)

• Negative test for selected drugs of abuse at Screening (does not include alcohol) and at Check-in (does include alcohol)

• Negative hepatitis panel (including hepatitis B surface antigen and hepatitis C virus antibody and negative human immunodeficiency virus (HIV) antibody screens

• Females must be nonpregnant, nonlactating, and either postmenopausal (defined as no menstrual period for at least 12 months and confirmed by a serum follicle-stimulating hormone (FSH) level of ≥40 milli-international units (mIU/mL), surgically sterile (e.g., bilateral oophorectomy, salpingectomy, and/or hysterectomy) for at least 90 days prior to Screening, or must have undergone bilateral tubal ligation and agree to use effective contraception. For all females, the pregnancy test results must be negative at Screening and Check-in

• Males will be surgically sterile for at least 90 days prior to Screening or when sexually-active with female partners of child-bearing potential will agree to use contraception from Check-in until 90 days following Discharge. Male participants must also be willing to refrain from donating sperm from Check-in until 90 days following Discharge

• Able to comprehend and willing to sign an informed consent form (ICF)

• A minimum of 1 to 2 bowel movements per day

Exclusion Criteria:

• Significant history or clinical manifestation of any metabolic, allergic, infectious, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder (as determined by the Investigator [or designee]) prior to Check-in

• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee) prior to Check-in

• History of stomach or intestinal surgery or resection that could alter absorption or excretion of orally administered drugs prior to Check-in, except that cholecystectomy, appendectomy, and hernia repair will be allowed if it was not associated with complications

• History or presence of an abnormal ECG that, in the Investigator's (or designee's) opinion, is clinically significant at Screening or Check-in

• History of orthostatic hypotension with or without syncope

• A sustained seated systolic blood pressure >150 millimeters of mercury (mmHg) or <90 mmHg or a diastolic blood pressure >90 mmHg or <50 mmHg at Screening or Check in. Blood pressure may be retested twice at intervals of 5 minutes. The out of range blood pressure values will be considered sustained if either the systolic or diastolic blood pressures are outside the stated limits after these 3 assessments

• History of alcoholism or drug addiction within 1 year prior to Check-in

• Use of any tobacco- or nicotine-containing products (including but not limited to cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to Check-in, or positive cotinine screen at Screening or Check-in

• Participation in more than 1 other radiolabeled investigational study drug trial within 12 months prior to Check-in. The previous radiolabeled study drug must have been received more than 6 months prior to Check-in for this study and the total exposure from this study and the previous study will be within the recommended levels considered safe, per United States (US) Title 21 Code of Federal Regulations (CFR) 361.1 (e.g., less than 5,000 millirem [mrem] whole body annual exposure)

• Exposure to significant radiation (e.g., serial x-ray or computed tomography scans, barium meal, current employment in a job requiring radiation exposure monitoring) within 12 months prior to Check-in

• Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 5 half-lives (if known) or 30 days prior to Check-in, whichever is longer

• Use of any prescription medications/products within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or designee)

• Use of any over-the-counter, nonprescription preparations (including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) within 7 days prior to Check-in, unless deemed acceptable by the Investigator (or designee)

• Poor peripheral venous access prior to Check-in

• Donation of whole blood from 56 days prior to Screening through Discharge, inclusive, or of plasma from 30 days prior to Screening through Discharge, inclusive

• Receipt of blood products within 2 months prior to Check-in

• Participant is at imminent risk of suicide (positive response to question 4 or 5 on the baseline Columbia-Suicide Severity Rating Scale (C-SSRS) or had a suicide attempt within 6 months prior to Screening

• Any acute or chronic condition that, in the opinion of the Investigator (or designee), would limit the particpant's ability to complete or participate in this clinical study

• Any other unspecified reason that, in the opinion of the Investigator (or designee) or Sponsor, makes the participant unsuitable for enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance Clinical Research Unit	Madison	Wisconsin	United States	53704

Sponsors and Collaborators

• Eli Lilly and Company
• CoLucid Pharmaceuticals

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)

• Study Protocol - Jan 23, 2017
• Statistical Analysis Plan - Jun 6, 2017

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03040362
• Other Study ID Numbers: 16884; H8H-CD-LAHH; COL MIG-110
• First Posted: Feb 2, 2017
• Last Update Posted: Jan 10, 2020
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lasmiditan

Study Results

Participant Flow

Pre-assignment Detail	Participants were preceded by an overnight fast (at least 10 hours) from food (not including water) before receiving a dose of [14C]-lasmiditan.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Period Title: Overall Study
STARTED	8
Received at Least 1dose of Study Drug	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Overall Participants	8
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39 (15.2)
Sex: Female, Male (Count of Participants)
Female	3 37.5%
Male	5 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 25%
Not Hispanic or Latino	6 75%
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 12.5%
White	7 87.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax)
Description	Maximum observed concentration based on plasma concentrations of lasmiditan.
Time Frame	Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)]	299 (36)

2. Primary Outcome

Title	Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax)
Description	Time to maximum concentration based on plasma concentrations of lasmiditan.
Time Frame	Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours pos-tdose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Median (Full Range) [hours (hr)]	2.02

3. Primary Outcome

Title	Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to Tlast (AUC[0-tlast])
Description	Area under concentration time curve (AUC) from Hour 0 to the last measurable concentration based on plasma concentrations of lasmiditan.
Time Frame	Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*h/mL)]	2100 (38)

4. Primary Outcome

Title	AUC Time Zero to Infinity (AUC0-∞) Blood/Plasma Ratio
Description	AUC time zero to infinity (0-∞) of total radioactivity in blood/AUC0-∞ of total radioactivity in plasma.
Time Frame	Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.948 (6)

5. Primary Outcome

Title	AUC Time Zero to Infinity (AUC0-∞) Plasma Lasmiditan/Total Radioactivity Ratio
Description	AUC time zero to infinity (0-∞) of lasmiditan in plasma/AUC0-∞ of total radioactivity in plasma.
Time Frame	Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours pos-tdose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	0.131 (18)

6. Secondary Outcome

Title	Pharmacokinetics - Cumulative Amount of Lasmiditan and Its Metabolites Excreted in Urine
Description	Amount of Lasmiditan and its metabolites (M3, M7, M8, (S,R)-M18, and (S,S)-M18) excreted in urine (Aeu) over sampling interval.
Time Frame	Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Lasmiditan	5.81 (1.12)
M3	1.62 (0.506)
M7	0.00224 (0.000902)
M8	132 (10.8)
(S,R)-M18	1.85 (0.534)
(S,S)-M18	0.445 (0.127)

7. Secondary Outcome

Title	Percentage of Lasmiditan Recovered in Urine, Relative to Dose Administered
Description	Percentage of lasmiditan recovered in urine (%UR), relative to dose administered calculated as %UR = 100 (amount of lasmiditan excreted in urine over a sampling interval (Aeu)/dose).
Time Frame	Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Mean (Standard Deviation) [% of lasmiditan dose]	2.91 (0.561)

8. Secondary Outcome

Title	Renal Clearance (CLR)
Description	Renal clearance is the volume of plasma completely cleared of lasmiditan by the kidneys per unit time and calculated as CLR = Aeu/AUC0-x (where Aeu = amount of lasmiditan excreted in urine over a sampling interval; x is the last interval collected; for lasmiditan only).
Time Frame	Pre-dose (-12 to 0 hours) and intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours post-dose

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had evaluable [14C]-lasmiditan PK data.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Mean (Standard Deviation) [liter per hour (L/hr)]	2.89 (1.12)

9. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Safety assessed from time of consent through end of study (up to 49 days). A summary of all reported serious adverse events (SAE) and other adverse events regardless of causality are provided in the Adverse Events module of this record.
Time Frame	Up to 49 days

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of the study drug and had at least 1 post-dose safety assessment.

Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
Measure Participants	8
Adverse Events (AEs)	5 62.5%
Serious Adverse Events (SAEs)	0 0%

Adverse Events

Time Frame	Up To 49 Days
Adverse Event Reporting Description	All enrolled participants who received at least one dose of study drug and had at least one post-dose safety assessment.
Arm/Group Title	[14C]-Lasmiditan
Arm/Group Description	Participants were administered a single oral dose of radiolabeled [14C]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution on Day 1.
All Cause Mortality
	[14C]-Lasmiditan
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	[14C]-Lasmiditan
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	[14C]-Lasmiditan
	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)
Ear and labyrinth disorders
External ear pain	1/8 (12.5%)	2
Gastrointestinal disorders
Diarrhoea	1/8 (12.5%)	1
Hypoaesthesia oral	1/8 (12.5%)	1
General disorders
Fatigue	1/8 (12.5%)	1
Feeling drunk	1/8 (12.5%)	1
Injury, poisoning and procedural complications
Post procedural contusion	2/8 (25%)	2
Procedural pain	2/8 (25%)	2
Procedural site reaction	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
Muscle spasms	1/8 (12.5%)	2
Nervous system disorders
Dizziness	2/8 (25%)	2
Sensory disturbance	1/8 (12.5%)	1
Psychiatric disorders
Euphoric mood	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea	2/8 (25%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Details of the study and its results shall not be publicized in any form without prior consent of the Sponsor. Such approval is necessary to prevent premature disclosure of trade secrets and other confidential information.