Pharmacokinetics and pharmacodynamics of intensive anti-tuberculosis treatment of tuberculous meningitis.Clin Pharmacol Ther 2020CP
The most effective anti-tuberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomised controlled trial comparing standard treatment with a regimen intensified by rifampin 15mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15mg/kg increased plasma and CSF exposures compared to 10mg/kg: day 14 plasma AUC0-24 increased from 48.2h∙mg/L (range 18.2-93.8) to 82.5h∙mg/L (range 8.7-161.0) and CSF AUC0-24 from 3.5h∙mg/L (range 1.2-9.6) to 6.0h∙mg/L (range 0.7-15.1). However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death and linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.