Silvia Grandoni (1), Nicola Cesari (2), Giandomenico Brogin (2), Paola Puccini (2) and Paolo Magni (1)
(1) Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Italy. (2) Chiesi Farmaceutici S.p.A., Parma, Italy.
Objectives: evaluating the impact of the particle size distribution of a polydisperse powder of inhaled drugs (compared with a monodisperse powder with particle size equal to the Mass Median Aerodynamic Diameter (MMAD)) on the lung and plasmatic concentration-time profiles derived with a WB-PBPK model.
Methods: administration of inhaled drugs was added to a previous developed and validated WB-PBPK model structure [1]. In particular, the lung was modelled considering its two main anatomical regions, the central (C) and the peripheral (P) one; each of these was further divided in three sub-regions to take into account the main physiological process occurring when a drug is inhaled, i.e. deposition, clearance, dissolution and absorption [2]. Hence, the resulting lung model comprises the following compartments for both the C and the P parts: the undissolved state compartment (to consider the amount of drug which deposits in the respiratory system), the dissolved state compartment (which represents the pulmonary Epithelial Lining Fluid (ELF), in which the drug dissolves) and the lung tissue. Each region is characterized by a different volume and surface and a different level of perfusion, since the C region is connected to the systemic circulation while the P region is connected to the pulmonary circulation.
Regarding the processes in which the inhaled compounds are involved, the dissolution was modelled with the Nernst-Brunner equation [3], the mucociliary clearance was included as acting in the C region only, as a first order process and the absorption was described as a first order process with an absorption rate constant depending on the surface area of the region and on the permeability of the drug.
The model was implemented in MATLAB™ in two versions which differ in the dissolution modelling only. The first version is structured as described above and considers all the particles as monodisperse and characterized by the MMAD. The second, structured to consider the particle size distribution (obtained as a fractional mass distribution from the impactor filter analysis), differs in the structure of the undissolved state compartments, which are divided in 9 sub-compartments (for both the C and P region), each of them containing an amount of monodisperse solid drug characterized by a certain diameter (taken as the mean diameter from those filtered from each filter section). The amount in each sub-compartment dissolves with a different rate due to its different particle size, following the Nernst-Brunner equation.
A series of intratracheal experiments were simulated in rats to compare the two models.
Different particle size distribution scenarios were reproduced, ranging from the realistic bell-shaped profile centred around the MMAD, to non-realistic U-shaped profiles in which the smaller and/or the larger particles are more represented. To compare the two versions of the model in similar conditions the particle size distributions were generated with the same MMAD.
Results: simulating with the U-shaped particle size distributions, deviations from the plasmatic and lung concentration-time profiles obtained using the MMAD only occur, in particular, the presence of earlier and higher plasma peaks is observed. Simulating with the bell-shaped distribution the differences are negligible.
Conclusions: with the here proposed WB-PBPK model, deviations from the PK profiles obtained considering the particles as monodispersed and represented by their MMAD occur only in some cases of non-realistic U-shaped distributions. Considering that actually the particle size distribution of the powders is typically bell-shaped and centred around the MMAD, the use of the MMAD only in the dissolution model seems to be, in this context, sufficient to describe the powder particle size in the lung dissolution process.
References:
[1] S. Grandoni, G. Bigoni, N. Cesari, P. Puccini, G. Brogin and P. Magni, «Evaluation of a minimal WB-PBPK platform supporting different routes of administration», PAGE 26 (2017), Abstract 7115.
[2] J. M. Borghardt, B. Weber, A. Staab e C. Kloft, «Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs», The AAPS Journal, vol. 17, n. 4, pp. 853-870, 2015.
[3] W. Nernst, «Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen», Zeitschrift für Physikalische Chemie, vol. 47, pp. 52-55, 1904.
Reference: PAGE 27 (2018) Abstr 8549 [www.page-meeting.org/?abstract=8549]
Poster: Drug/Disease Modelling - Absorption & PBPK