Pharmacokinetics of anti-tuberculosis drugs in multidrug resistant tuberculosis patients in India

Programmatic Management of multidrug resistant tuberculosis (MDR TB) services were introduced in the Indian TB control programme in 2007. A pharmacokinetic (PK) study of drugs used to treat MDR TB, namely levofloxacin (LFX), ethionamide (ETH), cycloserine (CS), pyrazinamide (PZA), moxifloxacin (MFX) and isoniazid (INH) was undertaken in adult MDR TB patients treated according to the prevailing guidelines in India. Factors influencing drug PK and end-of-intensive phase (IP) status were also determined. We recruited 350 MDR TB patients receiving anti-TB treatment (ATT) in the Indian Government programme in south India. At steady state, serial blood samples were collected, after supervised drug administration. Status at end of IP was noted from the programme records. Of the 303 patients for whom end-of-IP status was known, 214 were culture negative (responders), while 45 patients were either culture positive or required change of regimen or had died before completion of IP (non-responders). The median Cmax (2.0 vs 2.9g/ml; p = 0.005) and AUC0-12 (12.2 vs 17.0g/ml.h; p = 0.002) of ETH were significantly lower in non-responders than responders at IP. In multivariate logistic regression analysis, after excluding defaulters and adjusting for confounders, AUC0-12 of ETH significantly influenced end-of-IP status (aOR - 1.065; 95% CI: 1.001 - 1.134; p = 0.047). Drug doses used currently in the programme produced optimal drug concentrations in majority of patients. ETH played a major role in the MDR TB combination regimen and was a key determinant of end-of-IP status.