Research ArticleTuberculosis

Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis

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Science Translational Medicine  05 Dec 2018:
Vol. 10, Issue 470, eaau0965
DOI: 10.1126/scitranslmed.aau0965
  • Fig. 1 Experimental timeline and schematic.

    (A) Timeline of infection, antimicrobial treatment, and study procedures in rabbits. (B) 11C-rifampin for PET analysis (top) with three-dimensional (3D) volumes of interest (VOIs) drawn to measure the PET signal to generate time-activity curves (TACs) used to calculate AUC over 30 min (AUC0–30), or intravenous rifampin (bottom) for MS analysis. These results were used to develop a PK model to predict rifampin exposures in brain tissues. m/z, mass/charge ratio.

  • Fig. 2 Multidrug treatment in rabbits with experimentally induced TBM.

    (A) Transverse, coronal, and sagittal images from a representative infected rabbit pretreatment (week 0). BL seen on CT (left panels, yellow arrow) and 18F-FDG PET signal (right panels). (B) Standardized uptake values (SUVs) for 18F-FDG PET during treatment (data represent three to nine VOIs from two to six animals at each time point except week 6, where one VOI from a single animal is shown). (C to E) Gross pathology demonstrating BLs (yellow dotted outline) from animals 7 to 9 weeks after infection. (F) Hematoxylin and eosin (magnification, ×1; top, ×20) and acid-fast (bottom inset, ×100) staining of brain tissues [from (E)]. (G) CFU in the brain tissues are shown on a logarithmic scale. At least five animals were used for each group and time point except at weeks 4 (n = 4; treated group) and 6 (n = 1; untreated group). (H) CSF total protein and (I) glucose concentration over the treatment duration are shown. Controls refer to uninfected animals. At least three animals were used for each group and time point except at week 0 for protein and glucose assays in the control group (n = 2) and plasma glucose assays (n = 1 per group). CFU and CSF data are presented as means ± SD with statistical comparisons performed using two-tailed Student’s t test. Imaging data are presented as median ± IQR with statistical comparisons performed using two-tailed Mann-Whitney U test. Statistical significance is represented by *P < 0.05 or **P < 0.01.

  • Fig. 3 Dynamic 11C-rifampin PET and rifampin MS.

    (A) 3D reconstruction (left) and CT (top), 18F-FDG PET/CT (middle), and 11C-rifampin PET/CT (bottom) images of the sagittal, coronal, and transverse sections of the brain of a representative infected rabbit at 4 weeks of treatment. Outline of the brain compartment (dotted yellow line), BL (yellow arrow), and site of injection (white arrow) are shown. (B) TACs demonstrating 11C-rifampin exposures (Bq/ml) over 30 min in a BL from one animal imaged pretreatment (week 0) and at 4 and 6 weeks into treatment (corrected for weight and tracer dose). (C) 11C-rifampin brain/plasma AUC0–30 ratios in BLs [data represent three to nine VOIs from two to six animals at each time point except week 6, where one VOI from a single animal is shown]. (D) Rifampin concentration (μg/ml) and (E) tissue/plasma ratios (tissue30min ratio) from MS in postmortem samples at 30 min after rifampin intravenous dose at weeks 0 (n = 3 rabbits), 2 (n = 2), 3 (n = 1), and 4 (n = 3). (F) 11C-rifampin TAC from the same representative rabbit [from (A)]. (G) Rifampin concentration from all infected rabbits sampled (n = 9). Median and IQR are shown. *P < 0.05, **P < 0.01, and ***P < 0.001 by Wilcoxon signed rank test and two-tailed Mann-Whitney U test.

  • Fig. 4 Dynamic 11C-rifampin PET in a patient with TBM.

    (A) Brain MRI fluid-attenuated inversion recovery (FLAIR) and post-gadolinium sequences. (B) Dynamic 11C-rifampin PET/CT fusion images and (C) TACs demonstrating 11C-rifampin exposures (Bq/ml) over 40 min in the plasma and brain (lesion and unaffected). (D) Mass spectrometry results for plasma rifampin and 25-desacetyl rifampin in this patient.

  • Fig. 5 Plasma11C-rifampin and rifampin have similar PK characteristics.

    (A) Schematic representation of the PK model of oral rifampin from (12). Mean transit time (MTT), clearance (CL), volume of distribution (V), maximal increase in the enzyme production rate (Smax), rifampin concentration at which half the Smax is reached (SC50), and rate constant for first-order degradation of the enzyme pool (kenz). (B) Observed (purple dots) and model-predicted (black lines) rifampin plasma concentrations using digitized data from literature (table S4). (C) Observed (purple dots) and individual model predicted (black line) 11C-rifampin activity in plasma in representative TBM rabbits during treatment.

  • Fig. 6 PK–brain biodistribution rifampin model schematic and its goodness of fit in BLs.

    (A) Schematic of the developed PK–brain biodistribution model describing the distribution of rifampin into UB and BLs. Parameters include clearance (CL) from the central compartment, volume of distribution (VC) of the central compartment, clearance of unbound rifampin from plasma to UB or from plasma to BLs (Q), volume of distribution of UB (VUB), volume of distribution of BLs (VBL), partition/penetration coefficient (PC), partition/penetration coefficient at the start of treatment [week 0 (PC0)], partition/penetration coefficient beyond 2 weeks of treatment (PC≥2), MTT, maximal increase in the enzyme production rate (Smax), rifampin concentration at which half the Smax is reached (SC50), and rate constant for first-order degradation of the enzyme pool (kenz). (B) Observed (purple dots) and average PK model predicted (black lines) 11C-rifampin exposures in BLs in representative rabbits.

  • Fig. 7 Probability of target attainment for different rifampin doses in children.

    A population of 1000 children (2 to 11 years) between the World Health Organization (WHO) 25th and 75th percentile weight distribution was used to perform Monte Carlo simulations based on the developed PK–brain biodistribution model. Rifampin exposures in the lesions (Cmax) were then used to calculate the probability of target attainment, defined as the percentage that achieved rifampin Cmax values in the lesions above 4 μg/ml at the start of treatment or above 1 μg/ml subsequently.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/470/eaau0965/DC1

    Materials and Methods.

    Fig. S1. Organ bacterial burden in rabbits during treatment.

    Fig. S2. 11C-rifampin exposures in UB and plasma during treatment.

    Fig. S3. 11C-rifampin brain/plasma AUC0–30 ratios in UB during treatment.

    Fig. S4. Rifampin concentration using MS of UB during treatment.

    Fig. S5. Rifampin concentration by MS in brain and CSF in uninfected control rabbits.

    Fig. S6. 11C-rifampin brain/plasma AUC0–30 ratios in infected and uninfected control animals.

    Fig. S7. Plasma 11C-rifampin PET and rifampin MS correlation in patients with TB.

    Fig. S8. PK–brain biodistribution model goodness of fit in UB in rabbits.

    Table S1. Rabbit MS results.

    Table S2. Rabbit 11C-rifampin brain/plasma AUC0–30 ratios.

    Table S3. Parameter estimates from the rifampin PK enzyme turnover model.

    Table S4. Studies used for external validation of the plasma PK model.

    Table S5. Rifampin PK–brain biodistribution model parameter estimates and bootstrap results.

    Table S6. Projected mean rifampin exposure parameters (AUC0–24h and Cmax) in BLs in children at different weeks of treatment.

    Table S7. Projected rifampin exposures in the patient with TBM imaged in the current study.

    Table S8. Primary data.

    Movie S1. Whole-body 3D reconstruction of 11C-rifampin biodistribution in a rabbit with TBM.

    References (4659)

  • The PDF file includes:

    • Materials and Methods
    • Fig. S1. Organ bacterial burden in rabbits during treatment.
    • Fig. S2. 11C-rifampin exposures in UB and plasma during treatment.
    • Fig. S3. 11C-rifampin brain/plasma AUC0–30 ratios in UB during treatment.
    • Fig. S4. Rifampin concentration using MS of UB during treatment.
    • Fig. S5. Rifampin concentration by MS in brain and CSF in uninfected control rabbits.
    • Fig. S6. 11C-rifampin brain/plasma AUC0–30 ratios in infected and uninfected control animals.
    • Fig. S7. Plasma 11C-rifampin PET and rifampin MS correlation in patients with TB.
    • Fig. S8. PK–brain biodistribution model goodness of fit in UB in rabbits.
    • Table S1. Rabbit MS results.
    • Table S2. Rabbit 11C-rifampin brain/plasma AUC0–30 ratios.
    • Table S3. Parameter estimates from the rifampin PK enzyme turnover model.
    • Table S4. Studies used for external validation of the plasma PK model.
    • Table S5. Rifampin PK–brain biodistribution model parameter estimates and bootstrap results.
    • Table S6. Projected mean rifampin exposure parameters (AUC0–24h and Cmax) in BLs in children at different weeks of treatment.
    • Table S7. Projected rifampin exposures in the patient with TBM imaged in the current study.
    • References (4659)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S8 (Microsoft Excel format). Primary data.
    • Movie S1 (.mov format). Whole-body 3D reconstruction of 11C-rifampin biodistribution in a rabbit with TBM.

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