Population Pharmacokinetics of Rifampicin in Plasma and Cerebrospinal Fluid in Adults With Tuberculosis Meningitis

Abstract

Background: Several ongoing clinical trials are evaluating high-dose rifampicin (up to 35 mg/kg) for tuberculous meningitis (TBM). However, rifampicin pharmacokinetics at higher doses is not fully characterized, particularly in cerebrospinal fluid (CSF), the site of TBM disease.

Methods: In a randomized controlled trial, adults with HIV-associated TBM were assigned to experimental arms of high-dose rifampicin (oral, 35 mg/kg; intravenous, 20 mg/kg) plus linezolid, with or without aspirin, or a control arm that received the standard of care with 10 mg/kg of oral rifampicin. Rifampicin concentrations, including the unbound fraction, were measured on plasma samples, and CSF was collected on days 3 and 28 of study enrollment. Data were analyzed by nonlinear mixed effects modeling.

Results: In total, 400 plasma and 44 CSF rifampicin concentrations from 48 participants were used for model development. The median (range) age and weight were 39 years (25-78) and 60 kg (30-107). Rifampicin pharmacokinetics was best described by a 2-compartment disposition model with first-order transit oral absorption and elimination via saturable hepatic extraction. Typical clearance values for the standard dose for days 3 and 28 were 33.1 and 41.4 L/h, respectively; high-dose values were 46.1 and 70.2 L/h. The CSF-plasma ratio was approximately 6% and the equilibration half-life was 3.2 hours. Simulated standard-dose rifampicin did not reach CSF concentrations above the critical concentration for Mycobacterium tuberculosis.

Conclusions: CSF penetration with standard-dose rifampicin is low. Our findings support continued evaluation of high-dose rifampicin for TBM treatment.

Keywords: cerebrospinal fluid; high-dose rifampicin; modeling and simulation; population pharmacokinetics; tuberculosis meningitis.

Figure 1.

Illustration of the final structural model (from left to right): F_{oral,prehepatic} is the prehepatic oral bioavailability. k_tr is the first-order rate constant for drug passage through transit compartments. k_a is the first-order absorption rate constant. Q_H is the hepatic blood flow. F_H is the hepatic bioavailability. E_H is the hepatic extraction. V_H is the hepatic volume of distribution. V_c is the central volume of distribution. F_IV is the absolute intravenous bioavailability. V_p is the peripheral volume of distribution. Q is the intercompartmental clearance. K_m is the Michaelis-Menten constant. V_max is the maximum rate of elimination. C_H is the hepatic drug concentration. CL_int is the intrinsic clearance. PPC_plasma-CSF is the pseudo-partition coefficient, which represents the ratio of drug in CSF to plasma, and HL_plasma-CSF is the equilibration half-life between plasma and CSF, which describes how soon the change in plasma is reflected in the CSF. CSF, cerebrospinal fluid; IV, intravenous.

Figure 2.

Simulated typical concentration-time profiles for plasma and cerebrospinal fluid (CSF) for oral daily doses at steady state: high (35 mg/kg) and standard (10 mg/kg). The solid and dashed lines represent the high and standard doses, respectively. The horizontal dotted line shows the critical concentration (CC) value of rifampicin for Mycobacterium tuberculosis (0.5 mg/L) [21].

Figure 3.

Box and whisker plots show the secondary model-derived exposure parameters: area under concentration curve for 24 hours (AUC_0–24) and concentration at 24 hours postdose stratified by dose group. The dots represent individual values, and the whiskers are the 2.5th and 97.5th percentiles. Line, median; box, IQR. CSF, cerebrospinal fluid.