Effect of Non-Alcoholic Steatohepatitis (NASH) on the Pharmacokinetics of 99mTechnetium-Mebrofenin

NCT ID: NCT02235233

Last Updated: 2017-05-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2016-07-31

Brief Summary

This study is designed to investigate the effect of NASH (non-alcoholic steatohepatitis) on the disposition of 99mTechnetium(Tc)-mebrofenin and to relate changes in 99mTc-mebrofenin disposition to differences in the bile acid profile and Fibroscan Fibrosis Score of healthy subjects compared to patients with NASH.

Detailed Description

This will be an open-label, clinical study in male and female patients with NASH (n=10) and healthy volunteers (n=10) of any race and ethnicity investigating the effect of liver disease on the pharmacokinetics of 99mTechnetium-mebrofenin. The use of the gamma emitter 99m Tc- labeled mebrofenin will allow real-time assessment of hepatic exposure. To determine the differences between healthy subjects and patients with NASH, blood and hepatic concentrations will be analyzed by non-compartmental analysis. Additionally, serum bile acid samples and fibroscan data will be collected to determine whether the bile acid profile and/or fibroscan readings are different between healthy subjects and patients with NASH. Changes in 99mTc-mebrofenin will be correlated with the patient specific bile acid profile and fibroscan data. This study will increase our understating of the effect of liver disease on the disposition of medications that undergo transporter-mediated hepatic clearance.

Conditions

Non-alcoholic Steatohepatitis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Patients with NASH

Each subject will be injected with \~2.5 mCi of Technetium Tc 99M Mebrofenin

Group Type: EXPERIMENTAL

Technetium Tc 99M Mebrofenin

Intervention Type: DRUG

Each subject will be injected with \~2.5 mCi of Technetium Tc 99M Mebrofenin

Healthy Normal Volunteers

Each subject will be injected with \~2.5 mCi of Technetium Tc 99M Mebrofenin

Group Type: ACTIVE_COMPARATOR

Technetium Tc 99M Mebrofenin

Intervention Type: DRUG

Each subject will be injected with \~2.5 mCi of Technetium Tc 99M Mebrofenin

Interventions

Technetium Tc 99M Mebrofenin

Each subject will be injected with \~2.5 mCi of Technetium Tc 99M Mebrofenin

Intervention Type: DRUG

Other Intervention Names

Choletec

Eligibility Criteria

Inclusion Criteria

1. Healthy subjects: defined as being free from significant cardiac, pulmonary, gastrointestinal, hepatic, biliary, renal, hematological, neurological and psychiatric disease as determined by history, physical examination and clinical laboratory test results.

2. NASH subjects only: defined as those who have had a recent liver biopsy consistent with NASH without cirrhosis; NAS score >3.

3. Fluent and literate in English.

4. Willing and able to give informed consent prior to entering the study.

Exclusion Criteria

1. Donation of blood within last 30 days.

2. History of significant alcohol abuse (>20g/day) and/or illicit drug use, whether successfully treated or not.

3. Inability to abstain from alcohol for 48 hours prior to study visits.

4. Inability to fast for 8 hours prior to study sample collection.

5. Women who are pregnant, trying to become pregnant, or breast feeding.

6. Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the year prior to screening; these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens at doses greater than those used for hormone replacement or valproate/valproic acid

7. Type 2 diabetes treated with oral agents other than metformin; these include secretagogues, thiazolidinediones, alpha-glucosidase inhibitors, exenatide and pramlintide.

8. Current or recent use of bile acid sequestrants, bile acid derivatives (i.e. ursodiol) or fibric acid derivatives.

9. Serum blood glucose reading at study enrollment of >200 mg/dL.

10. Current use of antioxidants such as silymarin, vitamin C, glutathione, or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations, and special teas) within 30 days prior to screening. A multivitamin and vitamin E at standard doses will be allowed.

11. Previous liver biopsy that demonstrated presence of cirrhosis.

12. Radiologic imaging consistent with cirrhosis or portal hypertension.

13. Evidence of decompensated liver disease defined as any of the following: serum albumin <3.2 g/dL, total bilirubin > 1.5 mg/dL, or PT/INR > 1.3 times normal at screening, or history or presence of ascites, encephalopathy, or bleeding from esophageal varices.

14. Serum creatinine of 2.0 mg/dL or greater, or on dialysis, at screening.

15. History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis) that could affect the assessment of biomarkers (bile acids or inflammation).

16. Primary, secondary or extrahepatic malignancy.

17. History of bariatric surgery.

18. Participation in a research drug trial, exclusive of the SyNCH Phase I or II trials, within 30 days of screening.

19. BMI > 45 kg/m2 at screening (body weight is not within 20% of ideal body weight).

20. Inability or unwillingness to give informed consent or abide by the study protocol.

21. Estimated weekly strenuous exercise greater than 4 hours per week.

22. History or other evidence of illness or any other conditions or drug therapies that would make the patient, in the opinion of the investigator, unsuitable for the study (such as poorly controlled psychiatric disease, coronary artery disease, active gastrointestinal conditions or taking drugs known to interfere with bile acid synthesis or metabolism or the metabolism/transport of other drugs).

23. Undergone a radiographic procedure (other than dental X-rays), received radioactive substances, or handled radioactive materials in conjunction with employment within the last twelve months.

24. A history of hypersensitivity to 99mTc-mebrofenin, ultrasound gel, dairy products, or their excipients.

25. Consumed caffeine (coffee, tea, colas, and chocolate) within 24 hours of the study.

26. A history of tobacco use within 12 months of the study.

27. Serology positive for Hepatitis B, Hepatitis C or HIV at screening.

28. A history of any gastrointestinal or hepatobiliary surgery or disorder.

Healthy Subjects:

1. Taking concomitant medications, either prescription and non-prescription (including herbal products and over-the-counter medications), other than oral contraceptives and multivitamins (women stabilized on hormonal methods of birth control will be allowed to participate)

2. History or other evidence of liver disease in the opinion of the study investigators.

3. BMI > 30 kg/m2 at screening

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sidney Barritt, M.D., MSCR

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Jason R. Slizgi, B.S.

Role: STUDY_DIRECTOR

UNC School of Pharmacy

Kim Brouwer, PharmD, PhD

Role: STUDY_DIRECTOR

UNC School of Pharmacy

Josh Kaullen, Pharm.D.

Role: STUDY_DIRECTOR

UNC School of Pharmacy

Marijia Ivanovic, Ph.D.

Role: STUDY_DIRECTOR

UNC Department of Radiology

Paul Stewart, Ph.D.

Role: STUDY_DIRECTOR

UNC School of Public Health

Locations

UNC Hospitals

Chapel Hill, North Carolina, United States

Countries

United States

References

Pfeifer ND, Goss SL, Swift B, Ghibellini G, Ivanovic M, Heizer WD, Gangarosa LM, Brouwer KL. Effect of Ritonavir on (99m)Technetium-Mebrofenin Disposition in Humans: A Semi-PBPK Modeling and In Vitro Approach to Predict Transporter-Mediated DDIs. CPT Pharmacometrics Syst Pharmacol. 2013 Jan 2;2(1):e20. doi: 10.1038/psp.2012.21.

Reference Type: RESULT

PMID: 23887590 (View on PubMed)

Other Identifiers

2R01GM041935

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13-3362

Identifier Type: -

Identifier Source: org_study_id