Abstract
BackgroundFurther 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.MethodsMalawian 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.ResultsOne-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.ConclusionsWe 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.
Highlights
Whilst effective antibiotics for tuberculosis (TB) have been widely available for several decades, cure rates in high burden countries remain variable [1]
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
Plasma and sc intrapulmonary samples were collected 8 and 16 weeks into treatment and drug u concentrations measured in plasma, lung/airway epithelial lining fluid, and alveolar cells. n Population pharmacokinetic modelling generated estimates of drug exposure (Cmax and AUC) a from individual-level post-hoc Bayesian estimates of plasma and intrapulmonary M pharmacokinetics. ted RESULTS: One-hundred-and-fifty-seven patients (58% HIV co-infected) participated
Summary
Whilst effective antibiotics for tuberculosis (TB) have been widely available for several decades, cure rates in high burden countries remain variable [1]. Few existing healthy volunteer-based data suggest extensive variability in the pulmonary penetration of first-line anti-TB drugs, with potentially sub-therapeutic concentrations of rifampicin and isoniazid in epithelial lining fluid in a proportion of subjects [17,18,19,20,21,22]. These studies have limitations, as no patients with TB participated, drugs were given individually rather than in clinically relevant combinations, and sampling was limited to single fixed time-points. Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response
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