Pharmacokinetic Drug Interactions of AEGR-733 on Lipid-lowering Agents

A Phase II, Fixed-sequenced, Open- Label, Research Study to Assess Pharmacokinetic Drug Interactions of AEGR-733 on Lipid-lowering Therapies in Healthy Volunteers

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00359281

Enrollment

125

Registered

2006-08-02

Start date

2006-03-31

Completion date

2007-11-30

Last updated

2018-02-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Keywords

healthy volunteers

Brief summary

This phase II, open-label research study was conducted in 129 healthy volunteers. Each subject will be given one initial oral dose of one of 7 FDA-approved medications (probe drugs), followed by a 7 day period where subjects receive the study medication AEGR-733 at 10 or 60 mg. On study day 8 subjects will receive the second oral dose of the same probe drug that was given on day 1 and a last dose of AEGR-733 (total of 7 doses).Subjects will return in 1 week for a final safety visit. Each FDA- approved probe drug will be given to ten (10) or fifteen (15) subjects. Safety, pharmacokinetic and pharmacodynamic assessments will be performed.

Detailed description

Objectives: Primary: To evaluate the effects of low and high doses of AEGR-733 on the pharmacokinetics of 6 FDA-approved medications that are likely to be used in combination with AEGR-733 as assessed by: • Pharmacokinetic parameters: Cmax, Tmax, T1/2, and AUC (area under the curve). Secondary: To evaluate the safety of AEGR-733 in combination with other lipid lowering agents in healthy subject as assessed by: * Changes in associated liver enzymes AST, ALT and, Alkaline Phosphatase, & Total Bilirubin. * Changes in all reported adverse events. * To evaluate the effects of AEGR-733 in combination with other lipid lowering agents on the following lipids and lipoproteins: TC, LDL-C, VLDL, TG, HDL-C, ApoB and ApoAI. 4.0 STUDY DESIGN AND RATIONALE 4.1 STUDY DESIGN This is a single-center, phase II, clinical trial consisting of a eight (8) day open-label phase to assess the pharmacokinetic drug interactions of AEGR-733 on 6 probe drugs in healthy volunteers, followed by a one week safety visit. 105 subjects will be enrolled into this fixed-sequenced research study. Eligible subjects based on the screening visit will come to the GCRC for an inpatient visit (25-36 hr depending on if they come in evening before study day 1 or morning of). On the morning of study day 1, subjects will be assigned to one of 6 probe drugs(A-H below) and will take one dose of this medication. Timed blood samples will be drawn just before the administration of the probe drug and during the following times after drug administration (1,2,3,4,5,6,8,10,12,18, and 24 hrs). Prior to discharge after the 24 h blood sample, subjects will take an oral dose of AEGR-733 at 10 mg or 60 mg. Subjects will be given a 5 day supply of AEGR-733 at 10 mg or 60 mg to be taken once daily in the morning for the next 5 days (through day 7). On study day 8, subjects will take a final dose of AEGR-733 at 10 mg or 60 mg (total doses= 7) simultaneously with the same probe drug they took on day 1. Timed blood samples will be drawn just before the administration of the probe drug and AEGR-733 as well as 1,2,3,4,5,6,8,10,12,18, and 24 hours after study drug administration. After the 24 hour blood sample, subjects will be discharged. 15 subjects who participate in this study will receive dextromethorphan as the probe drug, which requires urine collection for 8 hours post dose. Blood for pharmacokinetic samples will not be collected on these subjects. Subjects receiving dextromethorphan may leave after the 8 hour urine collection at visits 2 and 3 (referred to as the inpatient visits). All subjects will come back 1 week later for a final visit to check safety lab parameters including liver transaminases and total bilirubin. Subjects will be instructed to abstain from drinking any alcoholic beverages once screened until study completion. Subjects who are not willing to comply with these requests will not be enrolled. The FDA-approved lipid-lowering therapies will include: A) Atorvastatin, 20 mg (n=15)and AEGR-733 10 mg B) Ezetimibe, 10 mg (n=10)and AEGR-733 10 mg C) Simvastatin, 20 mg (n=15)and AEGR-733 10 mg D) Rosuvastatin, 20 mg (n=10)and AEGR-733 10 mg E) Micronized fenofibrate, 145 mg (n=10)and AEGR-733 10 mg F) Atorvastatin, 20 mg (n=15) and AEGR-733 60 mg G) Rosuvastatin, 20 mg (n=15) and AEGR-733 60 mg H) Dextromethorphan, 30 mg (n=15) and AEGR-733 60 mg I) Extended Release Niacin, 1000 mg (n=20) and AEGR-733 10 mg

Interventions

DRUGatorvastatin

Atrovastatin 20 mg and AEGR-733 10 mg or 60 mg

DRUGsimvastatin

Simvastatin 20 mg and AEGR-733 10 mg or 60 mg

DRUGezetimibe

Ezetimibe 10 mg and AEGR-733 10 mg

DRUGfenofibrate

Micronized Fenofibrate 145 mg and AEGR-733 10 mg

DRUGdextromethorphan

Dextromethorphan 30 mg and AEGR-733 10 mg

DRUGExtended Release Niacin

1000 mg ER niacin and AEGR-733 10 mg

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

DIAGNOSTIC

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

Inclusion criteria

Males and non-pregnant/non-lactating female subjects between the ages of 18 and 70 who are in good overall health. To be eligible for enrollment in this study, patients must meet all of the following criteria: 1. Men and women between the ages of 18 and 70 2. Women of child-bearing potential, that is, women not surgically sterilized and between menarche and 1 year post menopause, must test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of non-medication birth control (for example, a reliable barrier method of birth control \[diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices\]; partner with vasectomy; or abstinence) during the study and for one month following the last dose of study drug. 3. Subjects must be in good overall health 4. Subjects must be able to comprehend and willing to provide a signed IRB approved Informed Consent Form. 5. Subjects must be willing to comply with all study-related procedures.

Exclusion criteria

1. Known atherosclerotic cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease 2. History of diabetes mellitus or fasting glucose \> 126 mg/dL at the screening visit. 3. History of a non-skin malignancy within the previous 5 years 4. Renal insufficiency as defined by creatinine \> 1.3 mg/dl 5. Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition 6. History of hypertension 7. Known coagulopathy and /or elevated PT/PTT \>1.5 x ULN 8. Oral history of HIV positive 9. Patients who have undergone any organ transplant 10. Known active fibrotic or cirrhotic disease; ALT or AST \> 1.5x ULN 11. Any major surgery within the previous 3 months 12. Individuals who currently use tobacco products or have done so in the previous 30 days 13. History of drug abuse (\< 3 years) 14. Regular use of alcoholic beverages (\> 7 drinks/day) 15. Subjects who do not agree to abstain from consuming alcoholic beverages during the entire study duration. 16. Body mass index (BMI) \> 30 kg/m2 or \< 18.5 kg/m2 17. Participation in an investigational drug study within 6 weeks prior to the screening visit 18. Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study will be excluded. 19. Currently taking any prescription, including oral contraceptives, or OTC medication regularly that cannot be stopped for at least 30 days prior to enrollment until completion of the study 20. Regular consumers of grapefruit juice, or have taken any medications known to be metabolized by CYP 3A4 within 4 weeks prior to the screening visit (ie. SSRIs, anti-fungals, anti-biotics, etc) 21. History of myalgia with a statin or unknown hypersensitivity to any statin, zetia, AEGR-733, or fenofibrate.

Design outcomes

Primary

Measure	Time frame	Description
AUC0-t Nicotinuric Acid	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for nicotinuric acid
Area Under Concentration-time Curve From 0 to Last Measureable Concentration (AUC0-t) Atorvastatin Acid (Lomitapide 10 mg)	0 to 24 hour	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for atorvastatin acid (Lomitapide 10 mg)
AUC0-t Simvastatin	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for simvastatin
AUC0-t Simvastatin Acid	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for simvastatin acid
AUC0-t Total Ezetimibe	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for total ezetimibe
AUC0-t Rosuvastatin (Lomitapide 10 mg)	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for rosuvastatin (Lomitapide 10 mg)
AUC0-t Fenofibric Acid	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for fenofibric acid
AUC0-t Atorvastatin Acid (Lomitapide 60 mg)	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for atorvastatin acid (Lomitapide 60 mg)
AUC0-t Rosuvastatin (Lomitapide 60 mg)	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for rosuvastatin (Lomitapide 60 mg)
AUC0-t Nicotinic Acid	0 to 24 hours	Geometric Mean Ratio ln(AUC0-t) Day 8/Day 1 for nicotinic acid

Secondary

Measure	Time frame	Description
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	Baseline to Day 8	Percent change from Baseline in LDL-C

Countries

United States

Participant flow

Recruitment details

The study was performed from 19 May 2006 to 20 November 2007 at 1 medical clinic within the United States.

Participants by arm

Arm	Count
Atorvastatin 20 mg + Lomitapide 10 mg One dose oral Atorvastatin 20 mg, Lomitapide 10 mg once daily 6 days then one dose oral Atorvastatin 20 mg and Lomitapide 10 mg	16
Simvastatin 20 mg + Lomitapide 10 mg One dose oral Simvastatin 20 mg, Lomitapide 10 mg once daily 6 days then one dose oral Simvastatin 20 mg and Lomitapide 10 mg	15
Ezetimibe 10 mg + Lomitapide 10 mg One dose oral Ezetimibe 10 mg, Lomitapide 10 mg once daily 6 days then one dose oral Ezetimibe 10 mg and Lomitapide 10 mg	10
Rosuvastatin 20 mg + Lomitapide 10 mg One dose oral Rosuvastatin 20 mg, Lomitapide 10 mg once daily 6 days then one dose oral Rosuvastatin 20 mg and Lomitapide 10 mg	10
Fenofibrate 145 mg + Lomitapide 10 mg One dose oral micronized Fenofibrate 145 mg, Lomitapide 10 mg once daily 6 days then one dose oral micronized Fenofibrate 145 mg and Lomitapide 10 mg	10
Atorvastatin 20 mg + Lomitapide 60 mg One dose oral Atorvastatin 20 mg, Lomitapide 60 mg once daily 6 days then one dose oral Atorvastatin 20 mg and Lomitapide 60 mg	15
Rosuvastatin 20 mg + Lomitapide 60 mg One dose oral Rosuvastatin 20 mg, Lomitapide 60 mg once daily 6 days then one dose oral Rosuvastatin 20 mg and Lomitapide 60 mg	18
Dextrometh-rophan 30 mg + Lomitapide 60 mg One dose oral Dextrometh-rophan 30 mg, Lomitapide 60 mg once daily 6 days then one dose oral Dextrometh-rophan 30 mg and Lomitapide 60 mg	15
ER Niacin 1000 mg + Lomitapide 10 mg One dose oral ER Niacin 1000 mg, Lomitapide 60 mg once daily 6 days then one dose oral ER Niacin 1000 mg and Lomitapide 60 mg	20
Total	129

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008
Overall Study	Adverse Event	1	0	0	0	0	0	1	0	0
Overall Study	Withdrawal by Subject	0	0	0	0	0	0	1	0	0

Baseline characteristics

Characteristic	Atorvastatin 20 mg + Lomitapide 10 mg	Total	ER Niacin 1000 mg + Lomitapide 10 mg	Dextrometh-rophan 30 mg + Lomitapide 60 mg	Rosuvastatin 20 mg + Lomitapide 60 mg	Atorvastatin 20 mg + Lomitapide 60 mg	Fenofibrate 145 mg + Lomitapide 10 mg	Rosuvastatin 20 mg + Lomitapide 10 mg	Ezetimibe 10 mg + Lomitapide 10 mg	Simvastatin 20 mg + Lomitapide 10 mg
Age, Continuous	26 years STANDARD_DEVIATION 7	28 years STANDARD_DEVIATION 10	29 years STANDARD_DEVIATION 11	27 years STANDARD_DEVIATION 9	31 years STANDARD_DEVIATION 13	27 years STANDARD_DEVIATION 8	24 years STANDARD_DEVIATION 3	31 years STANDARD_DEVIATION 13	29 years STANDARD_DEVIATION 9	29 years STANDARD_DEVIATION 12
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	15 Participants	2 Participants	3 Participants	1 Participants	3 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Black or African American	2 Participants	23 Participants	4 Participants	2 Participants	5 Participants	1 Participants	2 Participants	4 Participants	1 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 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	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	8 Participants	1 Participants	0 Participants	1 Participants	5 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	11 Participants	82 Participants	13 Participants	10 Participants	11 Participants	6 Participants	7 Participants	5 Participants	8 Participants	11 Participants
Region of Enrollment United States	16 participants	129 participants	20 participants	15 participants	18 participants	15 participants	10 participants	10 participants	10 participants	15 participants
Sex: Female, Male Female	7 Participants	53 Participants	9 Participants	6 Participants	9 Participants	5 Participants	2 Participants	2 Participants	3 Participants	10 Participants
Sex: Female, Male Male	9 Participants	76 Participants	11 Participants	9 Participants	9 Participants	10 Participants	8 Participants	8 Participants	7 Participants	5 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	8 / 16	8 / 15	6 / 10	3 / 10	6 / 10	12 / 15	15 / 18	11 / 15	18 / 20
serious Total, serious adverse events	0 / 16	0 / 15	0 / 10	0 / 10	0 / 10	0 / 15	0 / 18	0 / 15	0 / 20

Arm	Measure	Value (MEAN)	Dispersion
Atorvastatin 20 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-30.99 Percent Change	Standard Deviation 14.47
Simvastatin 20 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-26.43 Percent Change	Standard Deviation 17.77
Ezetimibe 10 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-28.36 Percent Change	Standard Deviation 12.53
Rosuvastatin 20 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-41.74 Percent Change	Standard Deviation 10.37
Fenofibrate 145 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-20.12 Percent Change	Standard Deviation 25.56
Atorvastatin 20 mg + Lomitapide 60 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-66.02 Percent Change	Standard Deviation 15.18
Rosuvastatin 20 mg + Lomitapide 60 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-63.20 Percent Change	Standard Deviation 18.59
Dextrometh-rophan 30 mg + Lomitapide 60 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-46.07 Percent Change	Standard Deviation 33.12
ER Niacin 1000 mg + Lomitapide 10 mg	Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	-20.89 Percent Change	Standard Deviation 15.17

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

Pharmacokinetic Drug Interactions of AEGR-733 on Lipid-lowering Agents

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Area Under Concentration-time Curve From 0 to Last Measureable Concentration (AUC0-t) Atorvastatin Acid (Lomitapide 10 mg)

AUC0-t Atorvastatin Acid (Lomitapide 60 mg)

AUC0-t Fenofibric Acid

AUC0-t Nicotinic Acid

AUC0-t Nicotinuric Acid

AUC0-t Rosuvastatin (Lomitapide 10 mg)

AUC0-t Rosuvastatin (Lomitapide 60 mg)

AUC0-t Simvastatin

AUC0-t Simvastatin Acid

AUC0-t Total Ezetimibe

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)