In:
European Respiratory Journal, European Respiratory Society (ERS), Vol. 58, No. 1 ( 2021-07), p. 2000955-
Abstract:
Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose escalation study in treatment-naive adult smear-positive patients with TB. Methods Patients received, in consecutive cohorts, 40 or 50 mg·kg −1 rifampicin once daily in monotherapy (day 1–7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between days 8 and 14. Results In the 40 mg·kg −1 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg −1 cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration–time curve from time 0 to 12 h (AUC 0–24 h ) for 50 mg·kg −1 compared with 40 mg·kg −1 ; 571 (range 320–995) versus 387 (range 201–847) mg·L −1 ·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg −1 (11% (range 8–17%)) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p 〈 0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg −1 : 14-day EBA −0.427 (95% CI −0.500– −0.355) log 10 CFU·mL −1 ·day −1 . Conclusion Although associated with an increased bactericidal effect, the 50 mg·kg −1 dose was not well tolerated. Rifampicin at 40 mg·kg −1 was well tolerated and therefore selected for evaluation in a phase IIc treatment-shortening trial.
Type of Medium:
Online Resource
ISSN:
0903-1936
,
1399-3003
DOI:
10.1183/13993003.00955-2020
DOI:
10.1183/13993003.00955-2020.Supp1
DOI:
10.1183/13993003.00955-2020.Shareable1
Language:
English
Publisher:
European Respiratory Society (ERS)
Publication Date:
2021
detail.hit.zdb_id:
2834928-3
detail.hit.zdb_id:
1499101-9
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