Robin J Svensson and Ulrika SH Simonsson
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: To apply the Multistate Tuberculosis Disease Model [1], linked to rifampicin pharmacokinetics (PK), to clinical Phase IIa colony forming unit (CFU) data in drug-susceptible pulmonary tuberculosis (TB) patients. In addition, to perform clinical trial simulations using the developed final model in order to predict retrospective clinical data as an external validation of the disease template approach.
Methods: CFU data from 24 patients [2] receiving 0 (n=4, negative control group), 5 (n=3), 10 (n=8) or 20 (n=8) mg/kg rifampicin were analyzed using non-linear mixed effects modeling implemented in NONMEM 7.3 [3]. A previously developed rifampicin population PK model [4] was linked to the Multistate Tuberculosis Disease Model, including fast-, slow- and non-multiplying as well as dead bacterial states, earlier developed using in vitro data [1]. Drug effect was implemented as exposure-response relationships tested at several effect sites in the Multistate Tuberculosis Disease Model, including inhibition of growth of the fast-multiplying state and as stimulation of the death rate of all states, both alone and in all possible combinations. External validation was performed by clinical trial simulation from the final model comparing the model predicted 95% prediction interval based on parameter uncertainty of the typical decline in CFU versus time to the mean±standard error of four datasets not used for model building.
Results: All system specific Multistate Tuberculosis Disease Model parameters were fixed to in vitro estimates except Bmax. The parameter Bmax described number of bacteria at stationary phase and was estimated throughout model building. All patients were assumed to have a stationary phase infection. Drug effect was best described by an on/off effect inhibiting growth of fast-multiplying bacteria in addition to slope models stimulating the death rate of slow- and non-multiplying bacteria. Stimulation of the death rate of the fast-multiplying state was not statistically significant. Clinical trial simulations predicted well four retrospective clinical trials using the final Multistate Tuberculosis Disease Model.
Conclusions: The Multistate Tuberculosis Disease Model was successfully applied to clinical data with rifampicin treated patients. Retrospective data was successfully predicted using clinical trial simulation with the final model which confirmed the utility of the approach in anti-tubercular drug development.
References:
[1] Clewe, O., Hu, Y., Coates, A. R. and Simonsson, U. S. H. A Semi-Mechanistic Pharmacokinetic-Pharmacodynamic Template Model for Studying Anti-tubercular Drug Effects In Vitro. Washington, DC, 5-9 September 2014, Abstr A-026. <http://www.icaaconline.com/php/icaac2014abstracts/data/papers/2014/A-026.htm>.
[2] Jindani, A., Aber, V. R., Edwards, E. A. and Mitchison, D. A. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am. Rev. Respir. Dis. 121, 939–949 (1980).
[3] Beal, S., Sheiner, L. B., Boeckmann, A. and Bauer, R. J. NONMEM User’s Guides. (1989-2013), Icon Development Solutions, Ellicott City, MD, USA, 2013.
[4] Smythe, W., Khandelwal, A., Merle, C., Rustomjee, R., Gninafon, M., Bocar Lo, M., Sow, O. B., Olliaro, P. L., Lienhardt, C., Horton, J., Smith, P., McIlleron, H. and Simonsson, U. S. H. A semimechanistic pharmacokinetic-enzyme turnover model for rifampin autoinduction in adult tuberculosis patients. Antimicrob. Agents Chemother. 56, 2091–2098 (2012).
Acknowledgements: This work was funded by Innovative Medicines Initiative Joint Undertaking, grant agreement n°115337. The authors are grateful for the sharing of data by Dr Amina Jindani. This work was supported by a grant from Vetenskapsrådet, Sweden.
Reference: PAGE 24 () Abstr 3520 [www.page-meeting.org/?abstract=3520]
Poster: Drug/Disease modeling - Infection