Evaluating Drug Deposition Patterns from Turbuhaler® in Healthy and Diseased Lung Models of Preschool Children.

The efficacy of pediatric oral drug delivery using dry powder inhalers, such as Turbuhaler®, is dependent on the age and health of the test subjects. The available clinical data for these studies is scant and rarely provide correlations between the health condition and the regional lung deposition. In particular, the data and the correlations for pre-school children are minimal. Deposition simulations were performed using the newly developed Quasi-3D whole lung model to analyze the effect of health conditions on the regional lung deposition from the Turbuhaler® in 3-year-old children. The healthy lung model was created from CT scan data. Cystic-fibrosis models were created by uniformly constricting the airways to various degrees. The simulated drug deposition outcomes were validated against the available experimental data. The results show that, while the dose deposited in the lungs exhibits minor variations, the Peripheral:Central (P/C) ratio is strongly affected by both the health condition and the inflow variations. The above ratio is reduced by ~30% for the severely diseased case, compared to its healthy counterpart, for the same inhalation profile. This indicates that lower doses reach the peripheral lung, in pediatric cystic-fibrosis subjects, thus requiring a larger therapeutic dose.

Predicting the Disposition of the Antimalarial Drug Artesunate and Its Active Metabolite Dihydroartemisinin Using Physiologically Based Pharmacokinetic Modeling.

Artemisinin-based combination therapies (ACTs) have proven to be effective in helping to combat the global malaria epidemic. To optimally apply these drugs, information about their tissue-specific disposition is required, and one approach to predict these pharmacokinetic characteristics is physiologically based pharmacokinetic (PBPK) modeling. In this study, a whole-body PBPK model was developed to simulate the time-dependent tissue concentrations of artesunate (AS) and its active metabolite, dihydroartemisinin (DHA). The model was developed for both rats and humans and incorporated drug metabolism of the parent compound and major metabolite. Model calibration was conducted using data from the literature in a Bayesian framework, and model verification was assessed using separate sets of data. Results showed good agreement between model predictions and the validation data, demonstrating the capability of the model in predicting the blood, plasma, and tissue pharmacokinetics of AS and DHA. It is expected that such a tool will be useful in characterizing the disposition of these chemicals and ultimately improve dosing regimens by enabling a quantitative assessment of the tissue-specific drug levels critical in the evaluation of efficacy and toxicity.