Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB

R. E. Aarnoutse, G. S. Kibiki, K Reither, H. H. Semvua, F Haraka, C. M. Mtabho, S. G. Mpagama, J van den Boogaard, I. M. Sumari-de Boer, C Magis-Escurra, M Wattenberg, J. G. M. Logger, L. H. M. te Brake, M Hoelscher, S. H. Gillespie, A Colbers, P. P. J. Phillips, G Plemper van Balen, M. J. Boeree, for the PanACEA consortium
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Background. In a multiple dose ranging trial we have previously evaluated higher doses of rifampicin in patients for two weeks. The objectives of the current study were to administer higher doses of rifampicin for a longer period to compare pharmacokinetics, safety/tolerability and bacteriological activity of such regimens.

Methods. In a double-blinded, randomized, placebo-controlled, phase II clinical trial ( NCT00760149) 150 Tanzanian TB patients were randomized to receive either 600 (approximately 10 mg/kg), 900 or 1200 mg rifampicin combined with standard doses of isoniazid, pyrazinamide and ethambutol administered daily for two months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. Bacteriological response was assessed by culture conversion in liquid and solid media.

Results. Geometric mean total exposures (AUC0-24h) were 24.6, 50.8 and 76.1 h*mg/L in the 600 mg, 900 mg and 1200 mg group respectively, reflecting a non-linear increase in exposure with the dose (p<0.001). Grade 3 events occurred in only 2 patients in the 600 mg arm, 4 patients in the 900 and 5 patients in the 1200 mg arm. No significant differences in bacteriological response were observed.

Conclusions: Higher daily doses of rifampicin (900 and 1200 mg) resulted in a more than proportional increase in rifampicin exposure in plasma, were safe and well tolerated when combined with other first-line TB drugs for two months, but did not result in improved bacteriological response in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampicin in follow-up trials.