In silico Prediction of Pharmacokinetic Parameters after Cisplatin Intravenous and Endotracheal Administration Using GastroPlusTM Software
Selma Chraibi1, Jessica Spires2, Karim Amighi1 & Nathalie Wauthoz1
1Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Boulevard du Triomphe, B-1050 Brussels, Belgium, [email protected]
2Simulation Plus, Inc., 42505 10th Street West, Lancaster 93534, United States of America (USA)
Introduction. Governmental health agencies encourage the development of in silico models that will bring in vitro data closer to in vivo data in a shorter time. GastroPlusTM (Simulation Plus, Lancaster, USA) is software that can simulate lung physiology to predict in vivo behaviour relying on in vitro data. The aim of this work was to use this tool to develop a cisplatin (CIS) model that can predict pharmacokinetic (PK) parameters after intravenous (IV) or endotracheal (EN) administration of a CIS solution or a CIS-based dry powder for inhalation (CIS-DPI). These simulations will help to develop new inhalable treatments against lung cancer. Methods. In vivo data came from the study made by Levet et al where a CIS–DPI and a CIS solution were administered to mice at 1.25 mg/kg using the EN or IV routes. PK parameters were generated from the in vivo data using the PKPlusTM module (Simulation Plus, Lancaster, USA) and were compared to the GastroPlusTM simulated results generated using only in vitro data. The pulmonary permeability (PP) and the systemic absorption rate (SAR) were optimized to develop a pulmonary model that best fits the in vivo data. Results. Default parameters provided by GastroPlusTM were suitable in obtaining IV and PK parameters that were close to the in vivo data. After adjusting PP and SAR, both the EN administration of CIS solution and CIS-DPI agreed with the pulmonary in vivo data. Conclusion. GastroPlusTM can predict CIS in vivo behaviour after IV or EN administration of CIS solution or CIS-DPI.