TY - JOUR A1 - Hartung, Niklas A1 - Borghardt, Jens Markus T1 - A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs JF - PLoS Computational Biology : a new community journal N2 - Author summary
The use of orally inhaled drugs for treating lung diseases is appealing since they have the potential for lung selectivity, i.e. high exposure at the site of action -the lung- without excessive side effects. However, the degree of lung selectivity depends on a large number of factors, including physiochemical properties of drug molecules, patient disease state, and inhalation devices. To predict the impact of these factors on drug exposure and thereby to understand the characteristics of an optimal drug for inhalation, we develop a predictive mathematical framework (a "pharmacokinetic model"). In contrast to previous approaches, our model allows combining knowledge from different sources appropriately and its predictions were able to adequately predict different sets of clinical data. Finally, we compare the impact of different factors and find that the most important factors are the size of the inhaled particles, the affinity of the drug to the lung tissue, as well as the rate of drug dissolution in the lung. In contrast to the common belief, the solubility of a drug in the lining fluids is not found to be relevant. These findings are important to understand how inhaled drugs should be designed to achieve best treatment results in patients.
The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics. Y1 - 2020 U6 - https://doi.org/10.1371/journal.pcbi.1008466 SN - 1553-734X SN - 1553-7358 VL - 16 IS - 12 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - de Wiljes, Jana A1 - Pathiraja, Sahani Darschika A1 - Reich, Sebastian T1 - Ensemble transform algorithms for nonlinear smoothing problems JF - SIAM journal on scientific computing N2 - Several numerical tools designed to overcome the challenges of smoothing in a non-linear and non-Gaussian setting are investigated for a class of particle smoothers. The considered family of smoothers is induced by the class of linear ensemble transform filters which contains classical filters such as the stochastic ensemble Kalman filter, the ensemble square root filter, and the recently introduced nonlinear ensemble transform filter. Further the ensemble transform particle smoother is introduced and particularly highlighted as it is consistent in the particle limit and does not require assumptions with respect to the family of the posterior distribution. The linear update pattern of the considered class of linear ensemble transform smoothers allows one to implement important supplementary techniques such as adaptive spread corrections, hybrid formulations, and localization in order to facilitate their application to complex estimation problems. These additional features are derived and numerically investigated for a sequence of increasingly challenging test problems. KW - data assimilation KW - smoother KW - localization KW - optimal transport KW - adaptive KW - spread correction Y1 - 2019 U6 - https://doi.org/10.1137/19M1239544 SN - 1064-8275 SN - 1095-7197 VL - 42 IS - 1 SP - A87 EP - A114 PB - Society for Industrial and Applied Mathematics CY - Philadelphia ER -