Chunli Chen(1), Fatima Ortega(2), Raquel Moreno(2, 3), Mats O. Karlsson(1), 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-UPV, Vitoria (Alava), Spain
Objectives: To develop a population pharmacokinetic (POPPK) model for rifampicin in mice and to optimize pharmacokinetic sampling schedule for rifampicin oral administration.
Methods: Rifampicin blood concentrations after different single oral doses, single intravenous and multiple oral administrations were used in the POPPK analysis. One sample from each mouse after single dosing administration and several samples from each mouse were available from multiple dosing administrations. All modeling were done using NONMEM 7.2. Model development was based on goodness of fit plots, objective function value, scientific plausibility, parameters precision and predict performance, assessed using Visual Predictive Check (VPC). In order to search for an informative design using potentially less animals, a simulation and re-estimation approach (SSE) was done using the final POPPK model with 1000 replicates for each scenario. The precision and bias of the simulation results were thereafter judged.
Results: A one compartment model with first-order absorption and elimination provided the best fit to the data. The volume of distribution was significantly lower for the lowest oral dose. Inter-individual variability (IIV) in absorption rate constant (ka) and clearance (CL) were estimated to 43.8% and 18.9%, respectively.
Conclusions: The final POPPK model described the data well. A framework was established for exploring different designs in order to collect adequate information for pharmacokinetic characterization and at the same time reduce the number of animals.
Acknowledgement: The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.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 European Directive 86/609/EEC and the GSK Policy on the Care, Welfare and Treatment of Animals.
Reference: PAGE 22 () Abstr 2706 [www.page-meeting.org/?abstract=2706]
Poster: Other Drug/Disease Modelling