Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC 0–24 ), maximum concentration (C max ), CSF concentration, and grade 3–5 adverse events. Results We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46–56). On day 2, geometric mean plasma AUC 0–24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 ( P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC 0–24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2–2.5) for IV-20 and 2.17 mg/L (1.6–2.9) for PO-35 regimens ( P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose ( P = .34). Conclusions Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC. Rifampicin is undetectable in the cerebrospinal fluid (CSF) of the majority of tuberculosis meningitis patients at standard dosing. Highdose rifampicin administered intravenously 20 mg/kg and orally 35 mg/kg resulted in therapeutic CSF rifampicin concentrations with no excess toxicity in a population consisting predominantly of people living with human immunodeficiency virus (HIV).
【저자키워드】 HIV, tuberculous meningitis, rifampicin, intensified therapy, TBM, 【초록키워드】 Trial, Open-label, Tuberculosis, Toxicity, outcome, CD4, adverse events, Randomized, serum, Adults, International, therapeutic, tuberculous meningitis, rifampicin, Patient, Meningitis, plasma, cerebrospinal fluid, Human immunodeficiency virus, patients, CSF, pharmacokinetic, Concentration, dose, AUC, Safe, intravenous, regimen, open-label trial, geometric mean, Standard of care, High-dose, interquartile range, Participants, Adverse, Primary outcome, minimal inhibitory concentration, 95% confidence interval, immunodeficiency virus, Primary outcomes, participant, C max, inhibitory concentration, intravenously, Standard-of-care, Administered, event, current, PK data, IMPROVE, Result, enrolled, not differ, performed, occurred, median, majority, sustained, with HIV, geometric, tuberculous, undetectable, would increase, 【제목키워드】 Human, tuberculous meningitis, rifampicin, oral, phase, Controlled,