Therapeutic drug monitoring of first-line anti-tuberculosis drugs: impact of dose modification on plasma drug concentrations in pulmonary and extrapulmonary tuberculosis.

BACKGROUND: Standard weight-based dosing of first-line anti-tuberculosis drugs does not consistently achieve therapeutic plasma concentrations in all patients. Inadequate drug exposure may contribute to poor treatment response, particularly in extrapulmonary and disseminated tuberculosis, where pharmacokinetic variability is more pronounced. Therapeutic drug monitoring (TDM) offers a strategy to individualize dosing and optimize plasma drug concentrations.

METHODS: This observational analytical study enrolled 100 patients with pulmonary, extrapulmonary, or disseminated tuberculosis, of whom 84 with complete TDM data were included in the final analysis. All patients received standard weight-based doses of rifampicin, isoniazid, and pyrazinamide. Plasma drug concentrations were measured after two weeks of anti-tuberculosis therapy (steady state) at 2 and 4 h following supervised drug administration. Patients with subtherapeutic concentrations underwent TDM-guided dose modification, followed by repeat plasma sampling at identical post-dose time points. Plasma drug concentrations before and after dose modification were compared, including subgroup analysis by acetylator status.

RESULTS: Among the 84 patients, 27.4% (n&#xa0;=&#xa0;23) had pulmonary tuberculosis, 58.3% (n&#xa0;=&#xa0;49) extrapulmonary tuberculosis, and 14.3% (n&#xa0;=&#xa0;12) disseminated disease. At baseline, subtherapeutic 2-hour plasma concentrations were observed in 67.9% (57/84) for rifampicin and 61.9% (52/84) for isoniazid, while 11.9% (10/84) had subtherapeutic pyrazinamide levels. Following TDM-guided dose modification, median rifampicin concentrations increased from 5.9&#xa0;mg/L (IQR 4.8-6.6) to 15.1&#xa0;mg/L (IQR 13.7-16.8), and median isoniazid concentrations from 2.3&#xa0;mg/L (IQR 1.9-2.6) to 6.2&#xa0;mg/L (IQR 5.3-6.9) (p&#xa0;<&#xa0;0.001 for both). Subtherapeutic exposure declined to 7.1% for rifampicin and 9.5% for isoniazid. Fast acetylators had significantly lower baseline isoniazid concentrations but showed marked improvement after dose escalation.

CONCLUSION: Subtherapeutic plasma concentrations of rifampicin and isoniazid are highly prevalent in patients with pulmonary, extrapulmonary, and disseminated tuberculosis receiving standard weight-based dosing. TDM-guided dose modification results in significant and clinically meaningful improvements in drug exposure. Selective incorporation of TDM into routine tuberculosis care may facilitate precision dosing, particularly in patients with extrapulmonary disease or suspected pharmacokinetic variability.