Isoniazid exposures and acetylator status in Indonesian tuberculous meningitis patients

Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia

“…We observed much higher exposures compared with those recorded in Indonesian DS-TB patients on the standard-dose isoniazid. 27 , 28 However, considering susceptibility of the Mycobacterium , 30 isoniazid exposures in this study were below targets in the majority of patients, with only <25% of patients achieving the targets for isoniazid AUC 0–24 /MIC ( n = 6/26; 23%) and C max /MIC ( n = 5/25; 19%). All of these patients harboured M. tuberculosis with low-level resistance to isoniazid.…”

“…The current study was part of an ongoing descriptive PK study of clofazimine in RR/MDR-TB patients in Indonesia that included 40 patients. Of note, previous PK studies among DS-TB patients in Indonesia indicated that a minimum of 20 patients was sufficient to describe isoniazid PK, 20 , 27 although in these studies acetylation status was not taken into account in the sample size calculation. Isoniazid AUC 0–24 and C max values were log-transformed prior to statistical analyses.…”

“…The overall AUC 0–24 and C max estimates for high-dose isoniazid in this study were compared with the overall estimates for standard-dose isoniazid previously reported in Indonesian adults with DS-TB (AUC 0–24 : 15.6–16.4 h·mg/L; and C max : 4.5 mg/L). 27 , 28 Next, considering isoniazid PK values associated with 90% of the maximum early bactericidal activity achieved in pulmonary DS-TB patients (AUC 10.5 h·mg/L and C max 2.19 mg/L), 29 and assuming an MIC of ≤0.125 mg/L for DS-TB with WT distributions, an AUC 0–24 /MIC target of 85 and C max /MIC target of 17.5 were used. 30 The proportion of patients achieving these PK/PD targets was assessed.…”