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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: warfarin sodium; Drug: mipomersen sodium; warfarin sodium

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States
      • PPD Development, LP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Kastle Therapeutics, LLC
• Collaborators: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: May 27, 2010
• First Submitted That Met QC Criteria: May 27, 2010
• First Posted (Estimate): May 28, 2010

Study Record Updates

• Last Update Posted (Estimate): August 3, 2016
• Last Update Submitted That Met QC Criteria: August 1, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: antisense; ApoB (Apolipoprotein B); LDL (low density lipoprotein); mipomersen; ISIS301012
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Anticoagulants; Warfarin; Mipomersen
• Other Study ID Numbers: MIPO2900509