Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions

Abstract

Standard antituberculosis (anti-TB) therapy requires the use of multiple drugs for a minimum of 6 months, with variable outcomes that are influenced by a number of microbiological, pathological, and clinical factors. This is despite the availability of antibiotics that have good activity against Mycobacterium tuberculosis in vitro and favorable pharmacokinetic profiles in plasma. However, little is known about the distribution of widely used antituberculous agents in the pulmonary lesions where the pathogen resides. The rabbit model of TB infection was used to explore the hypothesis that standard drugs have various abilities to penetrate lung tissue and lesions and that adequate drug levels are not consistently reached at the site of infection. Using noncompartmental and population pharmacokinetic approaches, we modeled the rate and extent of distribution of isoniazid, rifampin, pyrazinamide, and moxifloxacin in rabbit lung and lesions. Moxifloxacin reproducibly showed favorable partitioning into lung and granulomas, while the exposure of isoniazid, rifampin, and pyrazinamide in lesions was markedly lower than in plasma. The extent of penetration in lung and lesions followed different trends for each drug. All four agents distributed rapidly from plasma to tissue with equilibration half-lives of less than 1 min to an hour. The models adequately described the plasma concentrations and reasonably captured actual lesion concentrations. Though further refinement is needed to accurately predict the behavior of these drugs in human subjects, our results enable the integration of lesion-specific pharmacokinetic-pharmacodynamic (PK-PD) indices in clinical trial simulations and in in vitro PK-PD studies with M. tuberculosis.

Figures

Fig 1

Plasma concentration-time profiles of healthy rabbits following multiple (10 to 12) daily doses. (A) INH, 30 mg/kg; (B) RIF, 24 mg/kg; (C) PZA, 125 mg/kg; (D) MXF, 20 mg/kg. Average plasma concentrations with standard deviations (n = 4) are indicated.

Fig 2

Histograms of AUC ratios between tissue (lung or lesion) and plasma for each of the four study drugs. Predicted AUC ratios from the population analysis (PopPK) are compared with those computed using noncompartmental analysis (NCA) of data from the single-dose study with all four drugs administered together (dark gray bars). Individual AUC ratios from the population analysis were obtained from the effect compartment population PK model, based on all four lesion PK studies described in this work (light gray bars).

Fig 3

Composite photo of granuloma types sampled in this study. (A) Nonnecrotizing, predominantly cellular granuloma, with central epithelioid macrophages and no necrosis visible at dissection; cellular granulomas were typically ≤2 mm in diameter; (B) three or four coalescing nonnecrotizing granulomas that could not be divided into separate lesions during dissection; (C) necrotizing granuloma with central acellular region visible at dissection; (D) cavitating necrotic lesion which has become suppurative and macroscopically demonstrates a semiliquid core that oozes from the lesion during dissection. Histologically, the section shows infiltrating neutrophils and macrophages in the suppurative caseum. Bars, 500 μm.

Fig 4

Schematic picture describing the models for plasma pharmacokinetics and tissue penetration. The model for PZA included one absorption compartment. ka, absorption rate constant; V, oral volume of distribution; CL, clearance; V2, peripheral volume of distribution; Q, intercompartmental clearance; F, relative bioavailability for combination therapy; PC, penetration coefficient from plasma into lung or lesion; kpl-lung/lesion, distribution rate constant. Bioavailability (F) was fixed to 1 for all drugs but RIF, where the relative F was estimated for all single-dose studies and fixed to 1 for combination-therapy studies.

Fig 5

Observed plasma concentrations of INH, RIF, PZA, and MXF versus individual model-predicted concentrations. Solid line, line of identity.

Fig 6

Predicted concentration-time profiles for each individual animal are shown as solid lines. Observed concentrations are indicated by open circles. Data are shown for INH, RIF, PZA, and MXF in lung tissue and lesions.

Fig 7

Visual predictive check showing the predicted main trend (dashed lines) and 90% prediction interval (shaded areas) of plasma, lung, and lesion concentrations for INH at 50 mg/kg, MXF at 25 mg/kg, PZA at 125 mg/kg, and RIF at 30 mg/kg. Actual observations at the relevant doses are overlaid (open circles) and connected with a solid line.

Fig 8

Box plots of the ratios of individually predicted AUCs in lung and lesion tissue relative to plasma AUC for each drug. The box width is the interquartile range, with the horizontal line marking the median value. The whiskers indicate the maximum/minimum of ratios within 1.5 times the upper/lower quartiles. Observed data points falling outside this range are represented by open circles.