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

Abdelgawad N.; Chirehwa M.; McIlleron H.; Kanyama C.; Mwelase N.; Naidoo A.; Kumwenda J.; Nyirenda M.; Samaneka W.P.; Lama J.R.; Mohapi L.; Mave V.; Veloso V.G.; Valencia J.; Gupta A.; Hosseinipour M.C.; Scarsi K.; Denti P. · IJTLD Open (2026) · DOI: 10.5588/ijtldopen.25.0467

Resumen

BACKGROUND: 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). ME T H O D S: 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 pharmacoki-netic 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. R E S U L T S: Among 28 cases and 112 controls, the pro-portion of samples,LLOQ was 52% (cases) versus 45% (controls) for rifampicin and 20% (cases) versus 14% (controls) for pyrazinamide. Non-adherence was significantly higher in cases compared to controls for two pyrazinamide metrics: the week 4 LLOQ (P ¼ 0.050) and the week 2 2.5th percentile personalised threshold (P ¼ 0.023). C O N C L U S I O N: Poor adherence may have contributed to TB incidence in REMEMBER. While not definitive, personalised thresholds from model-based simulations remain useful for adherence assessment.