Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

Abstract

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/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 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2–93.8) to 82.5 hour·mg/L (range 8.7–161.0) in plasma and from 3.5 hour·mg/L (range 1.2–9.6) to 6.0 hour·mg/L (range 0.7–15.1) in CSF. 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 was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

“…For ethambutol, the PK was best described by a two-compartment model with first-order absorption and elimination, and this is consistent with previously published models (24,49,51). The elimination clearance in this study was higher than that in adult TB patients (24,49,51).…”

“…The values for rifampin plasma AUC 0–24 , corresponding to 50% of maximal survival (50% effective concentration [EC 50 ]), reported in those two studies were 86.4 mg×h/liter ( 21 ) and 171 mg×h/liter ( 22 ). Another study demonstrated that isoniazid exposure in plasma and cerebrospinal fluid (CSF) was associated with the risk of death in adults with TBM, estimating the EC 50 to be 7.03 mg×h/liter in both plasma and CSF ( 23 ). To date, no association between outcome and pyrazinamide and ethambutol exposures has been established in patients with TBM.…”

“…The rifampicin plasma exposure was much lower in this study compared to the estimated EC50 from Savic RM, et al (22) and Svensson EM, et al (23), which might explain that an effect was not found here. A recently published time-to-event model by Ding J, et al demonstrated that high isoniazid CSF peak concentration and exposure were associated with reduced risk of death in Vietnameseadult patients with TBM, thus the authors suggested that higher dose of isoniazid should be investigated(24).…”

“…The broken lines are the plasma/CSF targets of isoniazid, i.e. the lower blue line is the EC50 and the upper red line is the EC99 associated with survival in adults with TBM(24). Lower panels show the probability of achieving isoniazid steady-state target attainment (PTA) in plasma and CSF.…”

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

“…Rifampin 15mg/kg increased plasma and CSF exposures compared to 10mg/kg: day 14 plasma AUC 0–24 increased from 48.2h•mg/L (range 18.2–93.8) to 82.5h•mg/L (range 8.7–161.0) and CSF AUC 0–24 from 3.5h•mg/L (range 1.2–9.6) to 6.0h•mg/L (range 0.7–15.1). However, within the exposure range achieved, no relationship between rifampin exposure and survival was seen within the trial 41 . It is possible, as seen in the PTB model 34 and in TBM PK-PD model 38 , a rifampicin dose of greater than 15mg/kg is required to achieve exposures capable of reducing time to culture conversion and improving survival, which may explain the lack of exposure-response relationship seen in this trial.…”