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Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.
McCallum, Andrew D; Pertinez, Henry E; Else, Laura J; Dilly-Penchala, Sujan; Chirambo, Aaron P; Sheha, Irene; Chasweka, Madalitso; Chitani, Alex; Malamba, Rose D; Meghji, Jamilah Z; Gordon, Stephen B; Davies, Geraint R; Khoo, Saye H; Sloan, Derek J; Mwandumba, Henry C.
Afiliação
  • McCallum AD; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Pertinez HE; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
  • Else LJ; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • Dilly-Penchala S; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • Chirambo AP; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • Sheha I; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • Chasweka M; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Chitani A; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Malamba RD; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Meghji JZ; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Gordon SB; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Davies GR; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Khoo SH; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
  • Sloan DJ; Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.
  • Mwandumba HC; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
Clin Infect Dis ; 73(9): e3365-e3373, 2021 11 02.
Article em En | MEDLINE | ID: mdl-32856694
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Clin Infect Dis Assunto da revista: DOENCAS TRANSMISSIVEIS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Malauí

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Clin Infect Dis Assunto da revista: DOENCAS TRANSMISSIVEIS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Malauí