Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Intraoperative ICG plasma disappearance rate helps to predict absence of early postoperative complications after orthotopic liver transplantation

<p>Early postoperative complications after orthotopic liver transplantation (OLT) are a common problem in intensive care medicine. Adequate assessment of initial graft function remains difficult, however, plasma disaperance rate of indocyanine green (PDRICG) may have an additional diagnostic and prognostic value in this setting. We retrospectively evaluated the ability of intraoperative PDRICG values to predict absence of early postoperative complications in 62 subjects. PDRICG was measured non-invasively by pulse dye densitometry during surgery and was correlated with initial graft function. At the end of surgery, PDRICG was higher in patients without complications: 24.9 % min(-1) (n = 40) versus 21.0 % min(-1), (n = 22; p = 0.034). An area under the ROC curve (AUROC) for PDRICG was 0.70, while the AUROC for pH, lactate and PT at ICU admission were 0.53, 0.50 and 0.46, respectively. The AUROC of serum bilirubin and PT at postoperative day 5 were 0.68 and 0.49, respectively. The optimal cut-off PDRICG value for predicting absence of development early postoperative complications was determined to be 23.5 % min(-1) with 72.4 % sensitivity and 71.0 % specificity. Intraoperative point-of-care PDRICG measurement during OLT already predicts absence of early postoperative complications, better and earlier than clinically used laboratory parameters.</p>

Learning to coexist with wildfire

The impacts of escalating wildfire in many regions - the lives and homes lost, the expense of suppression and the damage to ecosystem services - necessitate a more sustainable coexistence with wildfire. Climate change and continued development on fire-prone landscapes will only compound current problems. Emerging strategies for managing ecosystems and mitigating risks to human communities provide some hope, although greater recognition of their inherent variation and links is crucial. Without a more integrated framework, fire will never operate as a natural ecosystem process, and the impact on society will continue to grow. A more coordinated approach to risk management and land-use planning in these coupled systems is needed