Intra-subject Variability of Pharmacokinetics
Conditions
Brief summary
Objectives: To evaluate the intra-subject variability of the pharmacokinetics (PK) of single oral capsule doses of 20 mg lomitapide.
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.
Interventions
DRUGlomitapide
20 mg dose
Sponsors
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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 |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lomitapide It will comprise of 2 single oral doses with at least a 14-day washout between doses.
lomitapide: 20 mg dose | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Day 1 | Withdrawal by Subject | 1 |
| Day 15 | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Lomitapide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 26.2 years STANDARD_DEVIATION 4.9 |
| Region of Enrollment United Kingdom | 15 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 13 |
| other Total, other adverse events | 4 / 15 | 1 / 13 |
| serious Total, serious adverse events | 0 / 15 | 0 / 13 |
Outcome results
Primary
AUC0-∞
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PK of Lomitapide | AUC0-∞ | Period 1 | 44.4 ng*hr/mL | Standard Deviation 19.9 |
| PK of Lomitapide | AUC0-∞ | Period 2 | 48.3 ng*hr/mL | Standard Deviation 23.4 |
| PK of M1 | AUC0-∞ | Period 1 | 68.3 ng*hr/mL | Standard Deviation 23.6 |
| PK of M1 | AUC0-∞ | Period 2 | 65.3 ng*hr/mL | Standard Deviation 24.1 |
| PK of M3 | AUC0-∞ | Period 1 | 330 ng*hr/mL | Standard Deviation 158 |
| PK of M3 | AUC0-∞ | Period 2 | 330 ng*hr/mL | Standard Deviation 181 |
Primary
AUC0-t
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PK of Lomitapide | AUC0-t | Period 2 | 44.0 ng*hr/mL | Standard Deviation 21.7 |
| PK of Lomitapide | AUC0-t | Period 1 | 40.2 ng*hr/mL | Standard Deviation 18.1 |
| PK of M1 | AUC0-t | Period 2 | 62.8 ng*hr/mL | Standard Deviation 23.3 |
| PK of M1 | AUC0-t | Period 1 | 65.8 ng*hr/mL | Standard Deviation 22.7 |
| PK of M3 | AUC0-t | Period 1 | 319 ng*hr/mL | Standard Deviation 153 |
| PK of M3 | AUC0-t | Period 2 | 319 ng*hr/mL | Standard Deviation 176 |
Primary
Cmax
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PK of Lomitapide | Cmax | Period 1 | 0.961 ng/mL | Standard Deviation 0.556 |
| PK of Lomitapide | Cmax | Period 2 | 1.02 ng/mL | Standard Deviation 0.843 |
| PK of M1 | Cmax | Period 1 | 2.34 ng/mL | Standard Deviation 0.593 |
| PK of M1 | Cmax | Period 2 | 2.20 ng/mL | Standard Deviation 0.664 |
| PK of M3 | Cmax | Period 1 | 23.6 ng/mL | Standard Deviation 7.08 |
| PK of M3 | Cmax | Period 2 | 22.8 ng/mL | Standard Deviation 9.33 |
Primary
t1/2
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PK of Lomitapide | t1/2 | Period 1 | 50.3 hr | Standard Deviation 7.56 |
| PK of Lomitapide | t1/2 | Period 2 | 47.8 hr | Standard Deviation 4.35 |
| PK of M1 | t1/2 | Period 1 | 38.3 hr | Standard Deviation 10.6 |
| PK of M1 | t1/2 | Period 2 | 38.0 hr | Standard Deviation 6.61 |
| PK of M3 | t1/2 | Period 1 | 46.9 hr | Standard Deviation 10.4 |
| PK of M3 | t1/2 | Period 2 | 41.2 hr | Standard Deviation 6.9 |
Primary
Tmax
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.
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PK of Lomitapide | Tmax | Period 1 | 4.0 hr |
| PK of Lomitapide | Tmax | Period 2 | 5.00 hr |
| PK of M1 | Tmax | Period 1 | 5.00 hr |
| PK of M1 | Tmax | Period 2 | 5.00 hr |
| PK of M3 | Tmax | Period 1 | 3.00 hr |
| PK of M3 | Tmax | Period 2 | 3.00 hr |
Primary
λz
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PK of Lomitapide | λz | Period 1 | 0.0141 1/hr | Standard Deviation 0.00196 |
| PK of Lomitapide | λz | Period 2 | 0.0146 1/hr | Standard Deviation 0.00139 |
| PK of M1 | λz | Period 1 | 0.0200 1/hr | Standard Deviation 0.00754 |
| PK of M1 | λz | Period 2 | 0.0189 1/hr | Standard Deviation 0.0041 |
| PK of M3 | λz | Period 1 | 0.0155 1/hr | Standard Deviation 0.0037 |
| PK of M3 | λz | Period 2 | 0.0172 1/hr | Standard Deviation 0.00272 |