Skip to content

Research at St Andrews

Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations

Research output: Contribution to journalArticle


Open Access permissions



Robin J Svensson, Elin M Svensson, Rob E Aarnoutse, Andreas H Diacon, Rodney Dawson, Stephen H Gillespie, Mischka Moodley, Martin J Boeree, Ulrika S H Simonsson

School/Research organisations


Background The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.

Methods Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.

Results The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25–10.3 days.

Conclusions A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.


Original languageEnglish
JournalJournal of Infectious Diseases
VolumeIn press
Early online date28 Apr 2018
Publication statusE-pub ahead of print - 28 Apr 2018

    Research areas

  • Pharmacodynamics, Tuberculosis, Pharmacokinetics, Patients, Time to positivity, Early bactericidal effect, Mycobacterium tuberculosis

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection

    Kloprogge, F., Hammond, R., Kipper, K., Gillespie, S. H. & Della Pasqua, O., 13 Sep 2019, In : Scientific Reports. 9, 8 p., 13228.

    Research output: Contribution to journalArticle

  2. A tuberculosis molecular bacterial load assay (TB-MBLA)

    Sabiiti, W., Mtafya, B. A., Alferes De Lima, D., Dombay, E., Baron, V. O., Azam, K., Orascova, K., Sloan, D. J. & Gillespie, S. H., 6 Sep 2019, (Accepted/In press) In : Journal of Visualized Experiments.

    Research output: Contribution to journalArticle

  3. Can phenotypic data complement our understanding of antimycobacterial effects for drug combinations?

    Kloprogge, F., Hammond, R., Copas, A., Gillespie, S. H. & Della Pasqua, O., 25 Aug 2019, In : Journal of Antimicrobial Chemotherapy. Advance article, 7 p.

    Research output: Contribution to journalArticle

  4. Toxicity related to standard TB therapy for pulmonary tuberculosis and treatment outcomes in the REMoxTB study according to HIV status

    Tweed, C. D., Crook, A. M., Dawson, R., Diacon, A. H., McHugh, T. D., Mendel, C. M., Meredith, S. K., Mohapi, L., Murphy, M. E., Nunn, A. J., Phillips, P. P. J., Singh, K. P., Spigelman, M. & Gillespie, S. H., 14 Aug 2019, In : BMC Pulmonary Medicine. 19, 9 p., 152.

    Research output: Contribution to journalArticle

  5. Model-based relationship between the molecular bacterial load assay and time-to-positivity in liquid culture

    Svensson, R. J., Sabiiti, W., Kibiki, G. S., Ntinginya, N. E., Bhatt, N., Davies, G., Gillespie, S. H. & Simonsson, U. S. H., 29 Jul 2019, In : Antimicrobial Agents and Chemotherapy. Early

    Research output: Contribution to journalArticle

Related by journal

  1. Strategies and challenges involved in the discovery of new chemical entities during early-stage tuberculosis drug discovery

    Coxon, G., Cooper, C., Gillespie, S. H. & McHugh, T., Mar 2012, Journal of Infectious Diseases, supplement, p. S1-7 8 p.

    Research output: Contribution to specialist publicationArticle

Related by journal

  1. Innovative Trial Designs Are Practical Solutions for Improving the Treatment of Tuberculosis

    Phillips, P. P. J., Gillespie, S. H., Boeree, M., Heinrich, N., Aarnoutse, R., McHugh, T., Pletschette, M., Lienhardt, C., Hafner, R., Mgone, C., Zumla, A., Nunn, A. J. & Hoelscher, M., 15 May 2012, In : Journal of Infectious Diseases. 205, p. S250-S257 8 p.

    Research output: Contribution to journalArticle

  2. Fragmented population structure of Plasmodium falciparum in a region of declining endemicity

    Anthony, T. G., Conway, D. J., Cox-Singh, J., Matusop, A., Ratnam, S., Shamsul, S., Singh, B. & Cox Singh, J., 1 May 2005, In : Journal of Infectious Diseases. 191, 9, p. 1558-1564 7 p.

    Research output: Contribution to journalArticle

  3. Iron Regulates Hepatitis C Virus Translation via Stimulation of Expression of Translation Initiation Factor 3

    Theural, I., Zoller, H., Obrist, P., Datz, C., Bachmann, F., Elliott, R. M. & Weiss, G., 15 Aug 2004, In : Journal of Infectious Diseases. 190, 4, p. 819-825 7 p.

    Research output: Contribution to journalArticle

ID: 253233657