Abstract
INTRODUCTION: Low or abnormal plasma concentrations of anti-tuberculosis drugs can be a major reason for treatment failure or the emergence of drug resistance. Acetylator status, which affects drug metabolism, plays a key role in determining drug bioavailability. This study aimed to perform therapeutic drug monitoring (TDM) of rifampicin and isoniazid and to evaluate the correlation between plasma drug concentrations and acetylator status among Indian patients receiving first-line antituberculosis therapy.
METHODS: Plasma concentrations of rifampicin and isoniazid were measured using in-house standardized high-performance liquid chromatography methods, while acetylator status was determined by conventional PCR of NAT2 gene.
RESULTS: Peak concentrations were estimated from 125 patients on first-line tuberculosis (TB) treatment. Among these, 56% exhibited subtherapeutic rifampicin concentrations and 28% had subtherapeutic isoniazid concentrations. Conversely, above normal (potentially toxic) concentrations were seen in 2% and 21% for rifampicin and isoniazid, respectively. Despite receiving the standard TB treatment regimen, only 62% of patients improved clinically, while 38% of patients continued harboring TB signs and symptoms, among which 6 patients (5%) developed rifampicin resistance during the treatment course. About 44% were slow acetylators, followed by 40% intermediate and 16% rapid acetylators. The acetylator status significantly influenced the plasma concentrations of both drugs. Slow acetylators had significantly higher isoniazid concentrations (p = 0.004) and lower rifampicin concentrations (p = 0.01) as compared to rapid acetylators.
CONCLUSION: Abnormal concentrations of rifampicin and isoniazid are prevalent and a major concern. Acetylator status influences plasma concentrations of rifampicin and isoniazid. Hence, determining acetylator status and performing TDM could be instrumental in optimizing and improving TB outcomes.