Anti-tuberculosis (TB) Drug Levels and Hepatotoxicity

Tuberculosis Clinical Trial

Official title:

Measurement of Drug Levels and Their Correlation With Hepatotoxicity During Antituberculosis Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00929786
• Other study ID #: SKS/DIH/01
• Secondary ID: sksharma@aiims.a
• Status: Completed
• Phase: N/A
• First received: June 29, 2009
• Last updated: November 9, 2009
• Start date: November 2007
• Est. completion date: June 2009

Study information

• Verified date: November 2009
• Source: All India Institute of Medical Sciences, New Delhi
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to evaluate plasma levels of hepatotoxic anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide plus significant metabolites) among patients on antituberculosis treatment (ATT) and compare the same among those who develop drug induced hepatitis on follow up versus those who do not.

Description:

Tuberculosis (TB) is a major health problem in both the developing and developed countries because of its resurgence in the immunosuppressed patients. World Health Organization (WHO) in 1993 declared tuberculosis to be a 'global emergency' with more than a third of the world's population infected. Globally 8.9 million new cases of tuberculosis occur annually, of which 1.8 million (20%) occur in India.

Short-course chemotherapy containing isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) has proved to be highly effective in the treatment of tuberculosis. One of its adverse effects is hepatotoxicity. It is the most common side effect leading to interruption of therapy. It is associated with mortality of 6-12% if these drugs are continued even after the onset of symptoms. Risk of hepatotoxicity is increased when these drugs are combined.

The time interval between the start of anti-TB drugs and appearance of hepatotoxicity varies from 3 to 135 days. In most cases hepatitis is evident within three months of start of antituberculosis treatment (ATT).

The pathogenesis of drug-induced hepatotoxicity (DIH) is still not entirely clear for most anti TB drugs including rifampicin. Hypersensitivity is a definite possibility Rifampicin induced hepatitis has been postulated to occur as a part of systemic allergic reaction and, due to unconjugated hyperbilirubinaemia as a result of competition with bilirubin for uptake at hepatocyte plasma membrane. DIH caused by rifampicin occurs earlier as compared to isoniazid. While a dose related toxicity may exist, a direct correlation between serum drug levels and hepatotoxicity has not been well reported. Thus the clinical relevance of therapeutic monitoring of serum rifampicin concentrations in managing DIH is still being explored.

Present study done to observe serum rifampicin, isoniazid, pyrazinamide level in patients on ATT and to compare it retrospectively between patients who develop drug induced hepatitis vs those who do not.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: June 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Patients diagnosed to be suffering from CatI/CatIII tuberculosis by a physician

2. Age: 16-65 years

3. Patient having normal baseline Liver function (AST/ALT1 < 50/50, serum bilirubin < 1.5 mg/dl)

Exclusion Criteria:

1. Patients receiving any other drug known to be metabolized by liver by cytochrome P450 3A4 or P-glycoprotein

2. Patients diagnosed to have acute viral hepatitis A, B, C, or E or carrier for HBV & HCV

3. Known HIV positive patients

4. Presence of chronic liver disease or renal insufficiency

5. Concomitant administration of other potential hepatotoxic drugs (methotrexate, phenytoin, valproate)

6. Chronic alcoholics who consume > 48 g of alcohol/day for at least one year

7. Pregnant women

8. Subjects not willing to participate

9. Known patients with malabsorption or drug abuse

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hepatitis
• Tuberculosis

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences	New Delhi	Delhi
India	All India Institute of Medical Sciences	New Delhi

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, New Delhi

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls		20 months	Yes
Secondary	Evaluation of plasma levels of any significant metabolites among cases and controls		20 months	No