A Study to Determine the Effects of Multiple Doses of Mipomersen (200 mg SC) on the Pharmacodynamics and Pharmacokinetics of Single-dose Warfarin

Study Overview
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Brief Summary
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The purpose of this study is to assess how blood clotting and thinning time is effected when a single dose of warfarin is given alone and when a single dose of warfarin is given with mipomersen; to assess the blood levels of a single dose of warfarin, a single dose of mipomersen, and a single dose of warfarin when given with mipomersen; and to assess the safety of mipomersen when given with or without warfarin.

Detailed Description
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This will be a Phase 1, open-label, single-sequence, 2-period, crossover study to determine the effect of multiple doses of mipomersen (200 mg SC given every other day for a total of 4 doses) on the PD and PK of warfarin and to evaluate the PK of mipomersen when administered alone and in combination with warfarin. Subjects will be admitted to the clinic on Day -1 until discharge from the clinic on Day 18 and return for outpatient visits on Days 19, 20, and 78. All subjects will receive a single 25-mg oral dose of warfarin given alone on Day 1 (designated the reference treatment). All subjects will then receive 200-mg SC doses of mipomersen given every other day on Days 8, 10, 12, and 14 (total of 800 mg mipomersen) with a single 25-mg oral dose of warfarin also given on Day 14 (combination designated the test treatment).

Official Title
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A Drug-Drug Interaction Study to Assess the Effects of Multiple Doses of Mipomersen (200 mg SC) on Single-Dose Warfarin (25 mg) Pharmacodynamics and Pharmacokinetics in Healthy Adult Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: warfarin sodium
* Drug: mipomersen sodium; warfarin sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent before any study-related procedure is performed. Body mass index (BMI) between 18 and 32 kg/m2, inclusive. No clinically significant abnormalities based on medical history, laboratory assessments, vital sign, 12-lead electrocardiogram (ECG) results, and physical examination. Subjects willing and able to follow a prescribed diet. Subjects have not consumed nicotine or nicotine-containing products for at least 6 months before Screening. Subjects are nonpregnant and nonlactating, surgically sterile, postmenopausal, abstinent, or the subject or partner is willing to use a reliable method of contraception during the study and for 5 months after mipomersen dosing. Exclusion Criteria: Poor metabolizer of warfarin as determined by CYP2C9 genotype testing. Clinically significant PT, aPTT, INR, protein C, protein S, or platelet count results or hematuria. Abnormal prolongation of skin bleeding time or a personal or family history of coagulation or bleeding disorders, vascular malformations including aneurysms, or venous thromboembolism. Active or recurring clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal, or metabolic disease. Active malignancy of any type other than nonmelanomatous skin malignancies. Use of any prescribed or over-the-counter concomitant medications within 14 days before the first dose of investigational product without approval of the Investigator and Sponsor. Positive test result for drugs of abuse, alcohol, or cotinine or history of alcohol abuse or drug addiction. Positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or HIV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: warfarin alone<br> | Drug: warfarin sodium<br>* 25 mg of warfarin oral (single dose)<br>* Other names: Coumadin®;|
| Experimental: warfarin with mipomersen<br> | Drug: mipomersen sodium; warfarin sodium<br>* 200 mg of mipomersen subcutaneous (SC) (4 doses) plus a single 25 mg of warfarin oral administered with the final mipomersen SC dose<br>* Other names: Coumadin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the effect curve (AUC), for INR (international normalized ratio), PT (prothrombin time), and aPTT (activated partial thromboplastin time) |  | Serial sampling up to 144 hours post dose | 
| Maximal Value (MAX) for INR, PT and aPTT |  | Serial sampling up to 144 hours post dose | 
| Time of maximal effect (Tmax) for INR, PT, and aPTT |  | Serial sampling up to 144 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Warfarin Plasma Pharmacokinetic parameters (AUC 0-t, AUC 0-inf, Maximum Concentration (Cmax)) |  | Serial PK sampling up to 144 hours post dose | 
| Mipomersen Plasma Pharmacokinetic parameters (AUC0-t, AUC0-inf, Cmax) |  | Serial PK sampling up to 24 hours post dose | 
| Incidence of treatment-emergent Adverse Events |  | Through Day 78 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ISIS301012, antisense, ApoB (Apolipoprotein B), LDL (low density lipoprotein), mipomersen