Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis

Junjie Ding, Nguyen Thuy Thuong Thuong, Toi Van Pham, Dorothee Heemskerk, Thomas Pouplin, Chau Thi Hong Tran, Mai Thi Hoang Nguyen, Phu Hoan Nguyen, Loc Phu Phan, Chau Van Vinh Nguyen, Guy Thwaites, Joel Tarning, Junjie Ding, Nguyen Thuy Thuong Thuong, Toi Van Pham, Dorothee Heemskerk, Thomas Pouplin, Chau Thi Hong Tran, Mai Thi Hoang Nguyen, Phu Hoan Nguyen, Loc Phu Phan, Chau Van Vinh Nguyen, Guy Thwaites, Joel Tarning

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.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Prediction‐corrected and variability‐corrected visual predictive check of the final population pharmacokinetic model for (a) rifampin plasma and (b) CSF concentration based on 1,000 stochastic simulations. Open circles represent the observations, and solid lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded areas represent the 95% confidence intervals around the simulated 5th, 50th, and 95th percentiles. CSF, cerebrospinal fluid.
Figure 2
Figure 2
Visual predictive check of the final population pharmacokinetic model for isoniazid plasma and CSF concentration in (a, c) fast and (b, d) slow metabolizers based on 1,000 stochastic simulations. Open circles represent the observations, and solid lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded areas represent the 95% confidence intervals around the simulated 5th, 50th, and 95th percentiles. CSF, cerebrospinal fluid.
Figure 3
Figure 3
Predicted Kaplan‐Meier curves for patients according to HIV, Glasgow coma scale (GCS), and isoniazid exposure.

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