Lu Gaohua1, Janak Wedagedera1, Ben Small1, Lisa Almond1, Klaus Romero2, Debra Hanna2, Dave Hermann3, Iain Gardner1, Masoud Jamei1, Amin Rostami-Hodjegan1,4
1 Simcyp Limited, Sheffield, UK,2 Critical Path Institute, Tucson Arizona, USA 3 Great Lakes Drug Development Inc, Michigan, USA 4 The University of Manchester, Manchester, UK
Objectives: The aim of this collaborative project between the Critical Path to TB Drug Regimens (CPTR) Consortium and Simcyp was to develop a mechanistic multi-compartment PBPK model that can be used to predict the time course of distribution of drugs into different regions of the lung after systemic administration.
Methods: To achieve this, the model should take into account drug movement across the alveolar capillary barrier (ACB) to be characterised by both passive permeability and active transport mechanisms and also to allow the physiological changes that occur following tuberculosis (TB) infection to be accounted for. The model includes various segments for airway and lobes, and each of the segments consists of 4 compartments representing the pulmonary capillary blood, pulmonary tissue mass, epithelial lining fluid and alveolar air. It accounts for pulmonary enzyme metabolism and incorporates transporter functionality at the basal and apical membrane of ACB. Major efforts were made to collate and meta-analyse data for lung physiological and anatomical parameters and any information on transporter abundance in the ACB from literature.
Results: The multiple-compartment lung model consists of 28 ordinary differential equations and c.a. 200 parameters implemented in Matlab Simulink®. Rifampicin, as a model compound, was selected and prior physicochemical and in vitro data along with passive permeability data from Cultured Human Airway Epithelial Cells (Calu-3) monolayer were used in the model building [1]. The predicted concentrations of pulmonary capillary blood, tissue mass and alveolar fluid after oral dose were comparable to the concentration of the systemic blood, epithelial lining fluid and alveolar cells observed clinically in adult subjects without TB [2]. TB-induced physiological parameter changes in the lung can impact the drug concentration-time profiles in different parts of the lungs and the model can effectively be used to investigate such changes and their impact on the drug response.
Conclusions: The developed lung model can provide a useful framework for investigation of new anti-TB drug’s pharmacokinetics and provides insight into the impact of different drug and system parameters on the drug disposition in different lobes of the lung. Moreover as the lung model can directly connect the dosing regimen of anti-TB drugs to the expected concentration at the site of action, it paves the way for better understanding of the potential drug actions in the human pulmonary system.
References:
[1] Tewes F, Brillault J, Couet W and Olivier JC (2008) Formulation of rifampicin-cyclodextrin complexes for lung nebulization. J Control Release 129:93-99.
[2] Goutelle S, Bourguignon L, Maire PH, Van Guilder M, Conte JE, Jr. and Jelliffe RW (2009) Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs. Antimicrob Agents Chemother 53:2974-2981.
Reference: PAGE 23 () Abstr 3113 [www.page-meeting.org/?abstract=3113]
Poster: Drug/Disease modeling - Absorption & PBPK