Chunli Chen (1), Gerjo J. de Knegt (2), Jurriaan E.M. de Steenwinkel (2), Ulrika SH Simonsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Erasmus MC, University Medical Centre Rotterdam, Department of Medical Microbiology & Infectious Diseases, Rotterdam, the Netherlands
Objectives: To use the Multistate Tuberculosis Disease Model for studying pharmacokinetics and pharmacodynamics (PKPD) of rifampicin (RIF) in a chronic tuberculosis (TB) mouse model.
Methods: One PK sample/animal was obtained in both healthy (n= 49) and infected mice (n= 18). Healthy mice were administered RIF (10 or 160 mg/kg) 5 days a week for 3 weeks where after the PK was obtained, which were pooled with PK data from infected mice. BALB/c mice were intratracheally infected with Mycobacterium tuberculosis Beijing-1585 strain at day 0 [1]. Rifampicin (5, 10, and 20 mg/kg orally) was administered daily for 4 weeks from day 15 after infection. Pharmacokinetic data was obtained at day 40. Mice were sacrificed at days 21, 28 and 42 and lungs were obtained, homogenized and plated to measure colony-forming unit (CFU) per mouse. Additional CFU were obtained in a separate group of infected mice treated for 3 weeks, from day 15 after infection, by RIF (80, 160 and 320 mg/kg, no PK) and sacrificed at day 35 after infection. One group of animal (n= 67) received no treatment (natural growth) and were sacrificed at days 1, 3, 7, 14 and 21 after infection. The population PK model was first developed and thereafter a Population PK Parameters and Data approach [2, 3] was used to link PK to the Multistate Tuberculosis Disease model [4] in order to describe the change in CFU in lungs over time using NONMEM [5]. Xpose [6] and PsN [7] was used for data exploration and visualization, model diagnostics, model comparison and visual predictive checks.
Results: A one-compartment model with first-order absorption and elimination provided the best fit to the PK data. Rifampicin oral clearance (CL/F) of infected mice treated 4 weeks was 3 times higher than in healthy mice received 3-week treatment. The Multistate Tuberculosis Disease Model [4] composed by fast- (F), slow- (S), non-multiplying (N) state bacteria and dead bacteria compartments, and drug effects were introduced in the model according to the mechanism of action. Bacterial movement between different states, except for the transfer from F to S, were fixed to corresponding transfer rates estimated in the in vitro study using Beijing-1585.
Conclusion: Most probably due to disease related effects, rifampicin CL/F was higher in infected mice, although auto-induction might contribute to a limited degree because of different treatment lengths, showing needs to obtain PK in the same animal as studying drug effects. The Multistate Tuberculosis Disease model successfully described anti-TB effects of RIF in a chronic mouse model.
References:
[1] De Steenwinkel JEM, Aarnoutse RE, de Knegt GJ, et al. (2013) Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model. Am J Respir Crit Care Med 187:1127–1134.
[2] Wade JR, Karlsson MO (1999) Combining PK and PD data during population PK/PD analysis. PAGE abstract 139.
[3] Zhang L, Beal SL, Sheiner LB (2003) Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn 30:387–404.
[4] Clewe O, Hu Y, Coates A, Simonsson USH (2014) A Semi-Mechanistic Pharmacokinetic-Pharmacodynamic Template Model for Studying Anti-tubercular Drug Effects In vitro. ICAAC abstract A-026.
[5] Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2013) NONMEM User’s Guides (1989-2013), Icon Development Solutions, Ellicott City, MD, USA.
[6] Jonsson EN, Karlsson MO (1999) Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64.
[7] Lindbom L, Pihlgren P, Jonsson EN, Jonsson N (2005) PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 79:241–257.
Acknowledgements: The research leading to these results has received funding from Vetenskapsrådet and the Innovative Medicines Initiative Joint Undertaking (www.imi.europe.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. All animal studies were ethically reviewed and carried out in accordance with the Dutch Animal Experimentation Act (1977) and the Guidelines on the Protection of Experimental Animals by the Council of the EC (1986). The Chinese Scholarship Council is acknowledged for scholarship to Ms. Chen.
Reference: PAGE 24 () Abstr 3511 [www.page-meeting.org/?abstract=3511]
Poster: Drug/Disease modeling - Infection