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