Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg-1 rifampicin
Lindsey H M Te Brake, Veronique de Jager, Kim Narunsky, Naadira Vanker, Elin M Svensson, Patrick P J Phillips, Stephen H Gillespie, Norbert Heinrich, Michael Hoelscher, Rodney Dawson, Andreas H Diacon, Rob E Aarnoutse, Martin J Boeree, PanACEA Consortium, Lindsey H M Te Brake, Veronique de Jager, Kim Narunsky, Naadira Vanker, Elin M Svensson, Patrick P J Phillips, Stephen H Gillespie, Norbert Heinrich, Michael Hoelscher, Rodney Dawson, Andreas H Diacon, Rob E Aarnoutse, Martin J Boeree, PanACEA Consortium
Abstract
Background: 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 (AUC0-24 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) log10CFU·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.
Trial registration: ClinicalTrials.gov NCT01392911.
Conflict of interest statement
Conflict of interest: L.H.M. te Brake has nothing to disclose. Conflict of interest: V. de Jager has nothing to disclose. Conflict of interest: K. Narunsky has nothing to disclose. Conflict of interest: N. Vanker has nothing to disclose. Conflict of interest: E.M. Svensson has nothing to disclose. Conflict of interest: P.P.J. Phillips reports grants from Ludwig Maximilian University of Munich, during the conduct of the study. Conflict of interest: S.H. Gillespie reports grants from the European and Developing Countries Clinical Trials Partnership and TB Alliance, outside the submitted work. Conflict of interest: N. Heinrich reports grants from the European and Developing Countries Clinical Trials Partnership and German Ministry for Education and Research, during the conduct of the study; other (paid presentation) from AstraZeneca, outside the submitted work. Conflict of interest: M. Hoelscher has nothing to disclose. Conflict of interest: R. Dawson has nothing to disclose. Conflict of interest: A.H. Diacon has nothing to disclose. Conflict of interest: R.E. Aarnoutse has nothing to disclose. Conflict of interest: M.J. Boeree has nothing to disclose.
Copyright ©ERS 2021. For reproduction rights and permissions contact permissions@ersnet.org.
Figures
References
- van Ingen J, Aarnoutse RE, Donald PR, et al. . Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis 2011; 52: e194–e199. doi:10.1093/cid/cir184
- Jayaram R, Gaonkar S, Kaur P, et al. . Pharmacokinetics–pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother 2003; 47: 2118–2124. doi:10.1128/AAC.47.7.2118-2124.2003
- Rosenthal IM, Tasneen R, Peloquin CA, et al. . Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. Antimicrob Agents Chemother 2012; 56: 4331–4340. doi:10.1128/AAC.00912-12
- de Steenwinkel JE, Aarnoutse RE, de Knegt GJ, et al. . Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med 2013; 187: 1127–1134. doi:10.1164/rccm.201207-1210OC
- World Health Organization . Global Tuberculosis Report 2018. Geneva, WHO, 2018.
- Boeree MJ, Diacon AH, Dawson R, et al. . A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med 2015; 191: 1058–1065. doi:10.1164/rccm.201407-1264OC
- Svensson RJ, Aarnoutse RE, Diacon AH, et al. . A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses. Clin Pharmacol Ther 2018; 103: 674–683. doi:10.1002/cpt.778
- Svensson RJ, Svensson EM, Aarnoutse RE, et al. . Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations. J Infect Dis 2018; 218: 991–999. doi:10.1093/infdis/jiy242
- Boeree MJ, Heinrich N, Aarnoutse R, et al. . High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis 2017; 17: 39–49. doi:10.1016/S1473-3099(16)30274-2
- Ewijk-Beneken Kolmer EWJ, Teulen MJA, van den Hombergh ECA, et al. . Determination of protein-unbound, active rifampicin in serum by ultrafiltration and ultra performance liquid chromatography with UV detection. A method suitable for standard and high doses of rifampicin. J Chromatogr B 2017; 1063: 42–49. doi:10.1016/j.jchromb.2017.08.004
- Ruslami R, Nijland HM, Alisjahbana B, et al. . Pharmacokinetics and tolerability of a higher rifampin dose versus the standard dose in pulmonary tuberculosis patients. Antimicrob Agents Chemother 2007; 51: 2546–2551. doi:10.1128/AAC.01550-06
- Donald PR, Sirgel FA, Venter A, et al. . Early bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther 2003; 1: 141–155. doi:10.1586/14787210.1.1.141
- Long JS. Regression Models for Categorical and Limited Dependent Variables. Thousand Oaks, Sage, 1997.
- Litjens CHC, Aarnoutse RE, van Ewijk-Beneken Kolmer EWJ, et al. . Protein binding of rifampicin is not saturated when using high-dose rifampicin. J Antimicrob Chemother 2019; 74: 986–990. doi:10.1093/jac/dky527
- McColl KE, Thompson GG, el Omar E, et al. . Effect of rifampicin on haem and bilirubin metabolism in man. Br J Clin Pharmacol 1987; 23: 553–559. doi:10.1111/j.1365-2125.1987.tb03091.x
- Chiou WJ, de Morais SM, Kikuchi R, et al. . OATP1B1 and OATP1B3 inhibition is associated with observations of benign clinical unconjugated hyperbilirubinemia. Xenobiotica 2014; 44: 276–282. doi:10.3109/00498254.2013.820006
- te Brake LHM, Russel FG, van den Heuvel JJ, et al. . Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters. Tuberculosis 2016; 96: 150–157. doi:10.1016/j.tube.2015.08.004
- Savic RM, Lu Y, Bliven-Sizemore E, et al. . Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother 2014; 58: 3035–3042. doi:10.1128/AAC.01918-13
- Srivastava S, Pasipanodya JG, Meek C, et al. . Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis 2011; 204: 1951–1959. doi:10.1093/infdis/jir658
- Pasipanodya JG, Srivastava S, Gumbo T. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy. Clin Infect Dis 2012; 55: 169–177. doi:10.1093/cid/cis353
- te Brake LHM, Ruslami R, Later-Nijland H, et al. . Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients. Antimicrob Agents Chemother 2015; 59: 3233–3239. doi:10.1128/AAC.03485-14
- Svensson EM, Svensson RJ, te Brake LHM, et al. . The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis 2018; 67: 34–41. doi:10.1093/cid/ciy026
- Velasquez GE, Brooks MB, Coit JM, et al. . Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. A randomized controlled trial. Am J Respir Crit Care Med 2018; 198: 657–666. doi:10.1164/rccm.201712-2524OC
- Liu Y, Pertinez H, Ortega-Muro F, et al. . Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria. J Antimicrob Chemother 2018; 73: 724–731. doi:10.1093/jac/dkx467
- De Jager V, Le Roux S, Mnunu M, et al. . Transcutaneous rifampicin concentration monitoring. Abstract presented a the 10th International Workshop on Clinical Pharmacology of Tuberculosis Drugs, Atlanta, GA, 2017.
- Susanto BO, Svensson RJ, Svensson EM, et al. . Rifampicin can be given as flat-dosing instead of weight-band dosing. Clin Infect Dis 2020; 71: 3055–3060. doi:10.1093/cid/ciz1202
- Phillips PP, Dooley KE, Gillespie SH, et al. . A new trial design to accelerate tuberculosis drug development: the phase IIC Selection Trial with Extended Post-treatment follow-up (STEP). BMC Med 2016; 14: 51. doi:10.1186/s12916-016-0597-3
- Aarnoutse RE, Kibiki GS, Reither K, et al. . Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB. Antimicrob Agents Chemother 2017; 61: e01054-17. doi:10.1128/AAC.01054-17
- te Brake LHM, Boeree MJ, Aarnoutse RE. Conflicting findings on an intermediate dose of rifampicin for pulmonary tuberculosis. Am J Respir Crit Care Med 2019; 199: 1166–1167. doi:10.1164/rccm.201811-2101LE
Source: PubMed