Intrapulmonary pharmacokinetics of first-line anti-TB drugs in Malawian tuberculosis patients

Andrew D McCallum, Henry E Pertinez, Laura J Else, Sujan Dilly-Penchala, Aaron P Chirambo, Irene Sheha, Madalitso Chasweka, Alex Chitani, Rose D Malamba, Jamilah Z Meghji, Stephen B Gordon, Geraint R Davies, Saye H Khoo, Derek J Sloan, Henry C Mwandumba

Research output: Contribution to journalArticlepeer-review


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, and alveolar cells. Population pharmacokinetic modelling generated estimates of drug exposure (Cmax and AUC) from individual-level post-hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.

Results: One-hundred-and-fifty-seven patients (58% HIV co-infected) 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 three compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in epithelial lining fluid and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6 (95% CI: 11.2-18.0) and 49.8-fold (95% CI: 34.2-65.3) higher in lining fluid than plasma respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cells: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.

Original languageEnglish
Article numberciaa1265
Pages (from-to)1-9
JournalClinical Infectious Diseases
VolumeAdvance articles
Early online date28 Aug 2020
Publication statusE-pub ahead of print - 28 Aug 2020


  • Tuberculosis
  • Pulmonary
  • Pharmacokinetics
  • Pharmacodynamics
  • Antibiotics
  • Antitubercular


Dive into the research topics of 'Intrapulmonary pharmacokinetics of first-line anti-TB drugs in Malawian tuberculosis patients'. Together they form a unique fingerprint.

Cite this