Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis
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, PanACEA Consortium, Anna Maria Mekota, Norbert Heinrich, Andrea Rachow, Elmar Saathoff, Michael Hoelscher, Stephen Gillespie, Georgette Plemper van Balen, Marloes Weijers, Angela Colbers, Rob Aarnoutse, Martin Boeree, Anna Bateson, Timothy McHugh, Kasha Singh, Robert Hunt, Alimuddin Zumla, Andrew J. Nunn, Patrick P. J. Phillips, Sunita Rehal, Rodney Dawson, Kim Narunsky, Andreas Diacon, Jeannine du Bois, Amour Venter, Sven Friedrich, Ian Sanne, Karla Mellet, Eefje de Jong, Gavin Churchyard, Salome Charalambous, Nomagugu Ndlovu, Vinodh Edward, Madulagotla Sebe, Lungile Mbata, Robert Wallis, Peter Mwaba, Nyanda Elias Ntinginya, Chacha Mangu, Christina Manyama, Gabriel Rojas-Ponce, Bariki Mtafya, Leonard Maboko, Frederick Haraka, Alphonce Kelemani, Khadija Said, Mohamed Sasamalo, Klaus Reither, Levan Jugheli, Noel Sam, Gibson Kibiki, Hadija Semvua, Stellah Mpagama, Abraham Alabi, Ayola Akim Adegnika, Evans Amukoye, Alphonse Okwera, 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, PanACEA Consortium, Anna Maria Mekota, Norbert Heinrich, Andrea Rachow, Elmar Saathoff, Michael Hoelscher, Stephen Gillespie, Georgette Plemper van Balen, Marloes Weijers, Angela Colbers, Rob Aarnoutse, Martin Boeree, Anna Bateson, Timothy McHugh, Kasha Singh, Robert Hunt, Alimuddin Zumla, Andrew J. Nunn, Patrick P. J. Phillips, Sunita Rehal, Rodney Dawson, Kim Narunsky, Andreas Diacon, Jeannine du Bois, Amour Venter, Sven Friedrich, Ian Sanne, Karla Mellet, Eefje de Jong, Gavin Churchyard, Salome Charalambous, Nomagugu Ndlovu, Vinodh Edward, Madulagotla Sebe, Lungile Mbata, Robert Wallis, Peter Mwaba, Nyanda Elias Ntinginya, Chacha Mangu, Christina Manyama, Gabriel Rojas-Ponce, Bariki Mtafya, Leonard Maboko, Frederick Haraka, Alphonce Kelemani, Khadija Said, Mohamed Sasamalo, Klaus Reither, Levan Jugheli, Noel Sam, Gibson Kibiki, Hadija Semvua, Stellah Mpagama, Abraham Alabi, Ayola Akim Adegnika, Evans Amukoye, Alphonse Okwera
Abstract
In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).
Keywords: drug safety; pharmacokinetics; rifampin; tuberculosis.
Copyright © 2017 American Society for Microbiology.
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Source: PubMed