Evaluation of a minimal WB-PBPK platform supporting different routes of administration
Silvia Grandoni (1), Giulia Bigoni (1), Nicola Cesari (2), Paola Puccini (2), Giandomenico Brogin (2), Paolo Magni (1)
(1) Department of Electrical, Computer and Biomedical Engineering, University of Pavia, via Ferrata 5, Pavia, I-27100, Italy. (2) Chiesi Farmaceutici S.p.A., via Palermo 26 A, Parma, 43122, Italy.
Objectives: Assessing in different species a minimal whole-body (WB) PBPK platform, implemented in Matlab from literature information, able to predict, from physiological literature parameters and drug in vitro data, concentration-time profiles of drugs administered following two different routes of administration: intravenous (IV) and oral (PO).
Methods: The WB-PBPK model was built considering twelve tissue compartments plus the ACAT model to describe the PO administration. No enzymatic reactions were explicitly modelled. The information required to simulate a new experiment are: the species (to upload the related physiological parameters derived from the literature [1,2]), some in vitro characteristics of the drug (e.g. acidic/basic/neutral or zwitterionic character, pKa, intrinsic solubility, logP, blood-plasma ratio), the route of administration, the type of input (bolus or infusion), the dose (or the rate, for the infusion). Two different strategies to calculate the partition coefficients were considered and are available: one based on the work of Poulin et. al [3] and the other based on Rodgers et al. [4,5]. The value of the Caco2 permeability must be specified to allow the calculation of the absorption parameters of the ACAT model. A function to compute the hepatic extraction ratio using the intrinsic microsomal clearance as input value is also considered.
Results: The platform was assessed on different drugs given IV and PO to rats, dogs and humans, by using in-house data and several clinical studies available in the literature [6-10]. The selected literature studies report both in vivo measurements and in silico profiles, some of them obtained with the Gastroplus software. The plasmatic concentration-time profiles of the new WB-PBPK platform reasonably describe the data and the computed pharmacokinetic parameters (i.e., AUC, Cmax, Tmax, CL and V) are, for almost all the considered studies, within two-fold range. Moreover, interestingly, the predictions of the implemented platform are similar to those obtained by GastroPlus and by the model in [6].
Conclusions: The implemented WB-PBPK platform, while requiring few basic in vitro information for simulating a new experiment, is able to reasonably describe both the in-house data and those reported in the selected literature studies. Moreover, for all the considered experiments, its performances are comparable to those of a more sophisticated PBPK model and modelling tool, such as GastroPlus.
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