Drug concentration at the site of disease in children with pulmonary tuberculosis

Abstract

Background: Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB.

Objectives: To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB.

Methods: We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions.

Results: Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions.

Conclusions: Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Figure 1.

Laser capture microdissection in a representative lymph node specimen. Haematoxylin and eosin-stained lymph node (frozen section) containing two lesions (A) and its corresponding serial section taken for laser capture microdissection (B). Regions 1–3 represent the areas dissected for drug quantification by LC-MS/MS. Example histology of the different areas dissected are shown and correspond to necrotic areas of the lesion (A, B1 and C), the cellular layer of the lesion (A, B2 and D), and a lymphocyte rich region (A, B3 and E). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Raw PK data for each drug in each lesion type. Log-scale concentration–time profiles are shown for five lesion types and four drugs by respective panel. Plasma concentrations over time for each individual were measured at multiple timepoints after the time of drug administration and before bronchoscopy or surgical decompression and are shown as individual lines of different colours. Lesion concentrations were measured at a single timepoint (time of resection) per subject and are represented by circles of different colours that correspond to their individual subject plasma line. The number of patients (and observations) for each lesion and drug are shown in the bottom, right corner of each image. Abbreviations: BAL, bronchoalveolar lavage; LN, lymph node; INH, isoniazid; RIF, rifampicin; PZA, pyrazinamide; EMB, ethambutol. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Simulated concentration–time profiles of children and adults relative to exposure target. Simulations for 1000 patients with the same representative characteristics were performed and their steady-state concentration–time profiles taken over 24 h. Red represents an 8.2 kg child aged 8.6 months with median and 95% CI. Blue represents simulated 60 kg adult profiles with available parameters from plasma [rifampicin (RIF; R), isoniazid (INH, H), pyrazinamide (PZA; Z) and ethambutol (EMB; E) from Smythe et al., Wilkins et al.^, and Jönsson et al., respectively] and lesion parameters (from Strydom et al.). Dosing for child was H = 120 mg, R = 120 mg, Z = 250 mg, E = 200 mg and for adult, H = 300 mg, R = 600 mg, Z = 1600 mg, E = 1100 mg. Yellow bands represent the distribution of PD exposure target selection: wild-type MIC for homogenized lymph node; intracellular macrophage IC₅₀ for cellular lesions (orange dashed line) and caseum MBC for the necrotic tissue (black dashed line). Abbreviations: MBC, minimum bactericidal concentration. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.