Study to Determine the Intra-subject Variability of Pharmacokinetics of Lomitapide in Healthy Subjects

• Sponsor: Aegerion Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01915771
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Days): 25
• Patients Per Site Per Month: 18.3

Study Details

Study Description

Brief Summary

Objectives:

To evaluate the intra-subject variability of the pharmacokinetics (PK) of single oral capsule doses of 20 mg lomitapide.

Condition or Disease	Intervention/Treatment	Phase
Intra-subject Variability of Pharmacokinetics	Drug: lomitapide	Phase 1

Detailed Description

This study will be a single centre, open-label study. It will comprise of 2 single oral doses with at least a 14-day washout between doses. Following the first dose subjects will be discharged from the unit for the remainder of the washout period. Subjects will be re-admitted to the unit on Day -1 (Period 2) and following an overnight fast they will be administered the second dose on Day 1 (Period 2). Subjects will be discharged from the unit following the 168 h PK blood draw.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1, Open-label, Crossover Study to Determine the Intra-subject Variability of the Pharmacokinetics of Single Oral CapsuleDose of 20 mg Lomitapide in Healthy Subjects
• Actual Study Start Date: Jul 29, 2013
• Actual Primary Completion Date: Aug 23, 2013
• Actual Study Completion Date: Aug 23, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lomitapide It will comprise of 2 single oral doses with at least a 14-day washout between doses.	Drug: lomitapide; 20 mg dose; Other Names: Juxtapid

Outcome Measures

Primary Outcome Measures

1. Cmax [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Maximum observed concentration of lomitapide and its metabolites, M1 & M3.

2. Tmax [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Time to reach maximum plasma concentration

3. AUC0-t [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Area under the concentration-time curve from hour 0 to the last measurable concentration of lomitapide and its metabolites, M1 & M3.

4. AUC0-∞ [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Area under the concentration-time curve extrapolated to infinity for lomitapide and its metabolites, M1 & M3.

5. λz [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Elimination rate constant estimated from individual linear regression of the terminal part of the log concentration vs time curve

6. t1/2 [Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.]

   Apparent terminal elimination half-life

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Subject is a non-smoking healthy male or female, aged between 18 and 40 years of age.

2. Subject has a BMI of 18.5 - 25 kg/m2.

3. Subject has total body weight between > 50 kg to ≤ 100 kg.

4. Subjects must agree to use acceptable methods of contraception.

5. All females, regardless of childbearing potential, must have a negative serum beta human chorionic gonadotropin pregnancy test at Screening and on admission.

6. In good health, determined by no clinically significant or relevant abnormalities identified by a detailed medical history & full physical examination.

7. No known history of hypersensitivity or previous intolerance to lomitapide.

8. Subjects must be capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form prior to undergoing any study-related procedures.

Exclusion Criteria:

1. Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion.

2. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs.

3. Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations.

4. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator;

5. Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening) such as a QTcF interval of >450 msec, a history of a prolonged QTc interval or Brugada syndrome.

6. History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, allergic, dermatological, metabolic, neurological, psychiatric or other disease.

7. History or laboratory evidence of Gilbert's syndrome.

8. Positive results in any of the serology tests for Hepatitis B Surface Antigen (HbsAg), anti-Hepatitis core antibody (anti-HBc Ig G [and anti-HBc IgM if IgG is positive], Hepatitis C antibodies (anti-HCV), and HIV 1 and 2 antibodies, (anti-HIV 1/2).

9. Use of any drugs of abuse within 6 months prior to admission.

10. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates and methadone) or from the alcohol breath test at screening and on admission (Day -1).

11. History or clinical evidence of alcohol or drug abuse within one year prior to admission.

12. Mentally handicapped.

13. Participation in a drug trial within 90 days prior to first drug administration.

14. Use of any prescription medication within 2 weeks prior to admission (Day -1), with the exception of the oral contraceptive pill.

15. Use of any substance inducing or inhibiting CYP3A4 enzymes within 30 days prior to admission (Day -1).

16. Use of any over-the-counter (OTC) medication (including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) within 7 days prior to admission (Day -1), unless deemed acceptable by the Investigator and Sponsor.

17. Use of alcohol-, grapefruit-, starfruit-, or caffeine-containing foods or beverages within 72 hours prior to admission and through Study Completion.

18. Donation of more than 500 mL of blood within 90 days prior to drug administration.

19. Receipt of blood products within 2 months prior to admission.

20. Poor peripheral venous access.

21. Use of any tobacco- or nicotine-containing products within 6 months prior to admission (Day -1).

22. Any acute or chronic condition, scheduled hospitalisation (inclusive of elective surgery during study), or scheduled travel prior to completion of all study procedures.

23. Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol.

24. Legal incapacity or limited legal capacity at screening.

25. Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with the study standardised menus.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Richmond Pharmacology	Croydon	Surrey	United Kingdom	CR7 7YE

Sponsors and Collaborators

• Aegerion Pharmaceuticals, Inc.

Investigators

• Study Chair: Mark Sumeray, MD, Aegerion Pharmaceuticals, Inc.
• Principal Investigator: Ulrike Lorch, MD, Richmond Pharmacology Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Aegerion Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01915771
• Other Study ID Numbers: AEGR-733-026; 2013-002692-17
• First Posted: Aug 5, 2013
• Last Update Posted: Mar 11, 2020
• Last Verified: Feb 1, 2020

Study Results

Participant Flow

Arm/Group Title	Lomitapide
Arm/Group Description	It will comprise of 2 single oral doses with at least a 14-day washout between doses. lomitapide: 20 mg dose
Period Title: Day 1
STARTED	15
COMPLETED	14
NOT COMPLETED	1
Period Title: Day 1
STARTED	14
COMPLETED	13
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Lomitapide
Arm/Group Description	It will comprise of 2 single oral doses with at least a 14-day washout between doses. lomitapide: 20 mg dose
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.2 (4.9)
Sex: Female, Male (Count of Participants)
Female	6 40%
Male	9 60%
Region of Enrollment (participants) [Number]
United Kingdom	15 100%

Outcome Measures

1. Primary Outcome

Title	Cmax
Description	Maximum observed concentration of lomitapide and its metabolites, M1 & M3.
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of Lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	0.961 (0.556)	2.34 (0.593)	23.6 (7.08)
Period 2	1.02 (0.843)	2.20 (0.664)	22.8 (9.33)

2. Primary Outcome

Title	Tmax
Description	Time to reach maximum plasma concentration
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of Lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	4.0	5.00	3.00
Period 2	5.00	5.00	3.00

3. Primary Outcome

Title	AUC0-t
Description	Area under the concentration-time curve from hour 0 to the last measurable concentration of lomitapide and its metabolites, M1 & M3.
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of Lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	40.2 (18.1)	65.8 (22.7)	319 (153)
Period 2	44.0 (21.7)	62.8 (23.3)	319 (176)

4. Primary Outcome

Title	AUC0-∞
Description	Area under the concentration-time curve extrapolated to infinity for lomitapide and its metabolites, M1 & M3.
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of Lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	44.4 (19.9)	68.3 (23.6)	330 (158)
Period 2	48.3 (23.4)	65.3 (24.1)	330 (181)

5. Primary Outcome

Title	λz
Description	Elimination rate constant estimated from individual linear regression of the terminal part of the log concentration vs time curve
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	0.0141 (0.00196)	0.0200 (0.00754)	0.0155 (0.00370)
Period 2	0.0146 (0.00139)	0.0189 (0.00410)	0.0172 (0.00272)

6. Primary Outcome

Title	t1/2
Description	Apparent terminal elimination half-life
Time Frame	Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose.

Outcome Measure Data

Analysis Population Description

Only 13 subjects who had evaluable PK data in both study periods were included in the PK analysis of lomitapide. One subject was excluded from PK analysis of M1 and M3 during Period 1 due to early termination. Another subject was excluded from PK analysis of M1 and M3 during Period 2 because the subject did not complete both Periods 1 and 2.

Arm/Group Title	PK of Lomitapide	PK of M1	PK of M3
Arm/Group Description	PK of Lomitapide Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M1 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)	PK of M3 Following a Single Oral Capsule Dose of 20 mg Lomitapide During Periods 1 and 2 (PK Set)
Measure Participants	13	14	14
Period 1	50.3 (7.56)	38.3 (10.6)	46.9 (10.4)
Period 2	47.8 (4.35)	38.0 (6.61)	41.2 (6.90)

Adverse Events

Arm/Group Title	Period 1		Period 2
Arm/Group Description	All 15 subjects who were enrolled in the study received at least one 20 mg dose of lomitapide and had assessments for the analysis of safety during Period 1.		Only 13 subjects who were enrolled in the study received 2 single daily doses of 20 mg lomitapide as planned (one dose in each of the two study periods). 2 subjects who only received one dose in Period 1 due to early withdrawal were not included in analysis of safety during Period 2.
All Cause Mortality
	Period 1		Period 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/13 (0%)
Serious Adverse Events
	Period 1		Period 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Period 1		Period 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/15 (26.7%)		1/13 (7.7%)
Blood and lymphatic system disorders
Lymphdenopathy	1/15 (6.7%)		0/13 (0%)
Gastrointestinal disorders
Abdominal Pain	1/15 (6.7%)		0/13 (0%)
Diarrhoea	3/15 (20%)		0/13 (0%)
Flatulence	1/15 (6.7%)		0/13 (0%)
Nausea	2/15 (13.3%)		0/13 (0%)
Abdominal Discomfort	2/15 (13.3%)		1/13 (7.7%)
Infections and infestations
Upper Respiratory Tract Infection	1/15 (6.7%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	1/15 (6.7%)		0/13 (0%)
Nervous system disorders
Headache	0/15 (0%)		1/13 (7.7%)
Dizziness	1/15 (6.7%)		0/13 (0%)
Psychiatric disorders
Anxiety	1/15 (6.7%)		0/13 (0%)
Skin and subcutaneous tissue disorders
Rash	1/15 (6.7%)		0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Described in contract