Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis

Abstract

Background: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.

Methods: Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.

Results: One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.

Conclusions: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

Keywords: antitubercular; pharmacodynamics; pharmacokinetics; pulmonary; tuberculosis.

Figure 1.

Summary concentration-time plots for rifampicin, isoniazid, pyrazinamide, and ethambutol in plasma, epithelial lining fluid, and alveolar cells from population means at steady state. To account for rifampicin protein binding, the red/pink-shaded area in the top-left panel illustrates plasma drug exposure for total drug (top line) or unbound drug (bottom line), assuming 80% protein binding in plasma and negligible protein binding in epithelial lining fluid. Plasma concentrations for isoniazid, pyrazinamide, and ethambutol are shown as total drug only. Concentrations at the different time points were calculated using the Bayesian posterior pharmacokinetic parameter value estimates and epithelial lining fluid to plasma (R_ELF) and alveolar cells to plasma (R_AC) ratios. The horizontal dotted line represents the plasma targets for therapeutic drug monitoring [29].

Figure 2.

Baseline drug sensitivity. Drug sensitivity in baseline sputum Mycobacterium tuberculosis isolates were determined using microtiter plates (n = 88). Pyrazinamide was not assessed due to its need for acidic test conditions. The MIC was recorded as the lowest concentration in the microtiter plate with no visible growth observed. The currently recommended critical concentration (breakpoint) is indicated by the vertical dashed line [32]. Abbreviation: MIC, minimum inhibitory concentration.