Pharmacokinetic Drug Interactions of AEGR-733 on Lipid-lowering Agents
Condition: Healthy
Study type: Interventional
Phase: Phase 2

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
    

Intervention name(s): atorvastatin; simvastatin; ezetimibe; fenofibrate; dextromethorphan; Extended Release Niacin
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Atrovastatin 20 mg and AEGR-733 10 mg or 60 mg; Simvastatin 20 mg and AEGR-733 10 mg or 60 mg; Ezetimibe 10 mg and AEGR-733 10 mg; Micronized Fenofibrate 145 mg and AEGR-733 10 mg; Dextromethorphan 30 mg and AEGR-733 10 mg; 1000 mg ER niacin and AEGR-733 10 mg
Intervention MeSH terms: Niacin; Dextromethorphan; Atorvastatin; Simvastatin; Ezetimibe; Fenofibrate
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: healthy volunteers