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Anti-tuberculosis (TB) Drug Levels and Correlation With Drug Induced Hepatotoxicity

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ClinicalTrials.gov Identifier: NCT01456845
Recruitment Status : Completed
First Posted : October 21, 2011
Last Update Posted : August 31, 2012
Sponsor:
Information provided by (Responsible Party):
S.K.SHARMA, All India Institute of Medical Sciences, New Delhi

Brief Summary:
The purpose of the study is to estimate plasma drug levels ( free and total drug levels ) of rifampicin and other antituberculosis drugs and compare these drug levels in patients who develop drug induced hepatotoxicity versus those who do not .The study hypothesis is that the ATT drug induced hepatotoxicity is related to free drug levels of rifampicin and other antituberculosis drugs .

Condition or disease
Hepatitis Tuberculosis

Detailed 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. Rifampicin is highly protein bound and hypoalbuminemia is a known risk factor for DIH ,so free drug levels in plasma has more significance than total drug levels in plasma.

Present study is done to estimate free and total drug levels of rifampicin and other antituberculosis drugs in patients on ATT and to compare it between patients who develop DIH vs those who do not and to assess the predicting ability of these drug levels in the subsequent development of drug induced hepatoxicity.


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Study Type : Observational
Actual Enrollment : 110 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Estimation of Plasma Free and Total Drug Levels of Rifampicin, Isoniazid and Pyrazinamide in Patients on Antituberculosis Therapy and Its Correlation With Development of Drug Induced Hepatotoxicity
Study Start Date : August 2010
Actual Primary Completion Date : June 2012
Actual Study Completion Date : June 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Group/Cohort
2

Cases - those patients who develop DIH while on regular treatment with anti-TB drugs.

Controls - patients who do not develop DIH while on regular treatment with anti-TB drugs.




Primary Outcome Measures :
  1. Evaluation of plasma levels of isoniazid, rifampicin, pyrazinamide among cases and controls [ Time Frame: 21 months ]

Secondary Outcome Measures :
  1. Evaluation of plasma drug levels and its correlation among cases and controls and to assess the ability of these drug levels to predict subsequent development of drug induced hepatoxicity [ Time Frame: 21 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Subjects: Patients with diagnosis of pulmonary/extrapulmonary Tuberculosis attending the out-patient department of the All India Institute of Medical Sciences, New Delhi, will form the study population.

Cases - those patients who develop DIH while on regular treatment with anti-TB drugs Controls - patients who do not develop DIH while on regular treatment with anti-TB drugs

Criteria

Inclusion Criteria:

  • Age: patients in the range between 18 to 65 years
  • Patients of either gender
  • Probable or confirmed cases of TB
  • Patients receiving daily antituberculosis drugs

Exclusion Criteria:

  • Patients with serological evidence of acute viral hepatitis A, B, C, or E and carriers of HBV and/or HCV
  • HIV positive patients
  • Presence of chronic liver disease or cirrhosis
  • Cognitive dysfunction
  • Terminally sick patients and unlikely to survive for 6-9 months
  • Concomitant administration of other potentially hepatotoxic drugs(Methotrexate, Phenytoin, phenobarbitone, carbamazepine ,valproate Atenolol, labetalol, Salicylates , allopurinol, quinine, quinidine, fluconazole, cimetidine, ethionamide, verapamil, probenecid, TCA, halothane)
  • Chronic alcoholics consuming >48 g/day for more 1 year
  • Patients not willing to give informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01456845


Locations
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India
All India Institute of Medical Sciences
New Delhi, India, 110029
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
Investigators
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Principal Investigator: Surendra K Sharma, MD,Ph.D All India Institute of Medical Sciences, New Delhi-110029, India

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: S.K.SHARMA, Professor and Head, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier: NCT01456845     History of Changes
Other Study ID Numbers: SKS/DIH/2011
First Posted: October 21, 2011    Key Record Dates
Last Update Posted: August 31, 2012
Last Verified: August 2012
Keywords provided by S.K.SHARMA, All India Institute of Medical Sciences, New Delhi:
Plasma levels
isoniazid
rifampicin
pyrazinamide
hepatoxicity
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Isoniazid
Pyrazinamide
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Molecular Mechanisms of Pharmacological Action
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents