Integration of preclinical and clinical knowledge to predict intravenous PK in human: Bilastine case study
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Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.
KeywordsBilastine Preclinical pharmacokinetics Quantitative pharmacology Allometric scaling Semiphysiological models Knowledge integration Drug development
This work was funded in part by the Ministry of Industry, Tourism and Commerce (formerly Ministry of Science and Technology) of Spain (PROFIT) and by the Department of Industry, Commerce and Tourism of the Basque Government (INTEK) and European Regional Development Fund (FEDER). Two of the authors (VV and IO) became involved thanks to support from the Department of Industry, Commerce and Tourism of the Basque Government (Ikertu) and the Torres Quevedo Programme of the Ministry of Science and Innovation, Spanish Government, respectively. This work is also part of the doctoral thesis of the corresponding author (directed by Dr. Rosario Calvo). Finally, the authors of this manuscript would also like to thank Dr. Aurelio Orjales for his contribution to these studies during his management of FAES Farma Research Department.
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