Population pharmacokinetic-pharmacodynamic modelling of rifampicin treatment response in a tuberculosis acute mouse model
Chunli Chen (1), Fatima Ortega (2), Joaquin Rullas-Trincado (2), Raquel Moreno (2, 3), Inigo Angulo (2), Santiago Ferrer (2), Ulrika SH Simonsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) GlaxoSmithKline Diseases of Developing World (DDW) Medicines Development Campus, Tres Cantos (Madrid), Spain; (3) Tecnalia Research&Innovation Foundation-Universidad del País Vasco (UPV), Vitoria (Alava), Spain
Objectives: To build a pharmacokinetic-pharmacodynamic (PKPD) model for rifampicin in a tuberculosis acute mice model.
Methods: Rifampicin blood concentrations after different single oral doses (1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg and 100 mg/kg), single intravenous (12 mg/kg) and multiple oral administrations (10 mg/kg for 3 days) were used in the population PK analysis. One sample from each healthy mouse (n=30) after single dosing administration and several samples from each healthy mouse were available from multiple dosing administrations (n=3). C57BL/6 mice were intratracheally infected with Mycobacterium tuberculosis H37Rv at day 0. Rifampicin was administered daily by oral gavage from day 1 to day 8. At day 9, 24 hours after last administration, mice were sacrificed. Their lungs were obtained, homogenized and plated to measure the colony-forming units (CFUs) per mouse. Pharmacodynamic data [1] from mice who received multiple daily rifampicin administrations up to 8 days were include in the PD model. The PK model was first developed and thereafter the PD model was developed using a sequential fit with fixed population PK parameters. All modeling were done using NONMEM, version 7.2 [2, 3]. Xpose was used for data exploration and visualization, model diagnostics and model comparison [4]. PsN [5] was used for visual predictive check (VPC) of models.
Results: A one compartment model with first-order absorption and elimination provided the best fit to the pharmacokinetic data. The volume of distribution was significantly lower for the lowest oral dose (1 mg/kg). Inter-animal variability (IIV) in absorption rate constant (ka) and clearance (CL) was estimated to 43.8% and 18.9%, respectively. The bioavailability was estimated to 67.6%. The PD model composed by bacteria compartments, and the drug effect was introduced in the model according to the mechanism of action of rifampicin.
Conclusions: The final PKPD model described the data well and can be used for studying drug effects in mice from mono-therapy as well as drug combinations.
References:
[1] Rullas J, García JI, Beltrán M, Cardona PJ, Cáceres N, García-Bustos JF, Angulo-Barturen I. Fast standardized therapeutic-efficacy assay for drug discovery against tuberculosis. Antimicrob Agents Chemother. 2010 May;54(5):2262-4
[2] Beal, S., Sheiner, L.B., Boeckmann, A., & Bauer, R.J., NONMEM User's Guides. (1989-2009)
[3] Icon Development Solutions, Ellicott City, MD, USA, 2009
[4] Jonsson EN, Karlsson MO. Xpose - an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. Jan 1999;58(1):51-64
[5] Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit - a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. Sep 2005;79(3):241-257
