Monitoring Drug Metabolism Of Mdr-tuberculosis Therapy

Multidrug resistant tuberculosis (MDR-TB) is a pandemic condition with an annual morbidity of close to half a million and mortality of over 200,000. This is a serious public health concern with MDR cases being reported across the globe with the highest prevalence in developing countries with the least capacity to deal with them. As the diagnosis of MDR-TB is difficult and often delayed and treatment is complicated the number of cases is likely to increase.

Critically, treatment failure accounts for 54% of total MDR-TB cases reported in 2016 and is the major cause of high mortality in drug resistant TB (WHO 2017). MDR is defined when the Mycobacterium tuberculosis (Mtb) causing TB is resistant to the two important first line drugs Rifampicin (R) and isoniazid (H). In this situation the standard drug regimen (for drug sensitive cases) no longer works and the condition of TB patient does not improve. The treatment regimen for MDR-TB (20-24 months) is lengthy and consists of drugs of lower efficacy and higher toxicity than frontline drugs. Many of these drug have been recognized as anti-mycobacterial for a long time but due to toxicity they have been replaced with other drugs in the standard TB regimen. Ineffective treatment of MDR-TB cases increases the chance of MDR-TB transmission and the development of extensive (XDR) or total (TDR) drug resistant variants.

The primary panacea to the problem of MDR-TB is new drugs with better efficacy and lower toxicity. However, in the absence of new drugs, better technical support to improve current MDR-TB monitoring and management practice will aid in tackling this issue significantly. Technical support both in terms of early prediction of treatment outcome and in monitoring compliance (linked to drug-toxicity) will hold the key in this regard. Recent studies show that the extent of disease, the BMI of the patient and treatment compliance are key determinants of treatment outcome in MDR-TB. While the first two parameters are interlinked and can be improved by early diagnosis, treatment compliance is influenced further by genetics, physical/physiological condition of the patients and drug tolerance. A tailor made, individualized treatment regimen is required to effectively treat MDR-TB and this is based on pathogen genetics (only in developed countries), drug sensitivity tests, and BMI of the patient. However, despite this personalized treatment regimen, low- compliance and failure of treatment is still significant as there is no clinical/biochemical parameter to predict treatment outcome. Indeed, such surrogates are absent even in drug susceptible TB.

Our hypothesize is that drug metabolic fingerprint will be an useful surrogate for treatment management in MDR-TB. Drug metabolites are important but less explored scientific entities in pharmacological research. Pharmacokinetic studies carried out during clinical trials primarily concentrate on the parent drug, its efficacy and toxicity. In fact many research article that include metabolism in their study synonymize metabolism with disappearance of parent drug without much emphasis on the generation of metabolized products. &Drug metabolism is primarily mediated by the hepatic enzymes cytochrome P40s (CYPs) and UDP-glucuronsyltransferase (UDPG). Huge inter-individual variation in drug metabolism kinetics is observed, due to heterogeneity of genotype of the patient, the patient s physiological condition, drug-drug interactions and nutrition. Since many of drug metabolites are the active therapeutic principle or potential toxic components, this drug metabolic heterogeneity has a direct influence on individual treatment outcomes. Post drug metabolic composition in human biofluids reflects both genetic and environmental determinants of drug metabolism and therefore provides integrated and precise information on the capacity of the drug to mediate its function.