Pharmacokinetic modelling as a tool to assess TB treatment adherence: application to the REMEMBER study

The REMEMBER (A5274) study found that the four-drug TB preventive regimen did not reduce mortality compared to isoniazid-only, raising adherence concerns. Using drug measurements and pharmacometrics, we assessed adherence in the four-drug arm by comparing participants who developed TB (cases) to those who did not (controls).

Using a 1:4 matched case-control design, we analysed stored blood samples at weeks 2, 4, and 8 since treatment start. Rifampicin and pyrazinamide were measured, and adherence was assessed using two thresholds: i) lower limit of quantification (LLOQ) and ii) personalised thresholds derived from pharmacokinetic simulations. Population pharmacokinetic models and Monte Carlo simulations were used to predict individualised thresholds assuming 100% adherence. Conditional logistic regression compared non-adherence between cases and controls.

Among 28 cases and 112 controls, the proportion of samples P = 0.050) and the week 2 2.5th percentile personalised threshold (P = 0.023).

Poor adherence may have contributed to TB incidence in REMEMBER. While not definitive, personalised thresholds from model-based simulations remain useful for adherence assessment.