Physiologically based pharmacokinetic modeling and simulation in pediatric drug development.

Increased regulatory demands for pediatric drug development research have fostered interest in the use of modeling and simulation among industry and academia. Physiologically based pharmacokinetic (PBPK) modeling offers a unique modality to incorporate multiple levels of information to estimate age-specific pharmacokinetics. This tutorial will serve to provide the reader with a basic understanding of the procedural steps to developing a pediatric PBPK model and facilitate a discussion of the advantages and limitations of this modeling technique.

A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam.

The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V(ss)) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5- and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V(ss) were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

Artificial nutritional support in patients with gastrointestinal fistulas.

Gastrointestinal (GI) fistulas allow abnormal diversions of GI contents, digestive juices, water, electrolytes, and nutrients from one hollow viscus to another or to the skin, potentially precipitating a wide variety of pathophysiologic effects. Mortality rates have decreased significantly during the past few decades from as high as 40% to 65% to 5.3% to 21.3% largely as a result of advances in intensive care, nutritional support, antimicrobial therapy, wound care, and operative techniques. The primary causes of death secondary to enterocutaneous fistulas have been, and continue to be, malnutrition, electrolyte imbalances, and sepsis, especially in high-output fistulas, which continue to have a mortality rate of about 35%. Priorities in the management of GI fistulas include restoration of blood volume and correction of fluid, electrolyte, and acid-base imbalances; control of infection and sepsis with appropriate antibiotics and drainage of abscesses; initiation of GI tract rest including secretory inhibition and nasogastric suction; control and collection of fistula drainage with protection of the surrounding skin; and provision of optimal nutrition by total parenteral nutrition (TPN) or enteral nutrition (EN) (or both). The role of nutrition support in the management of enterocutaneous fistulas as either TPN or EN is primarily one of supportive care to prevent malnutrition, thereby obviating further deterioration of an already debilitated patient. It has been shown in several studies that TPN has substantially improved the prognosis of GI fistula patients by increasing the rate of spontaneous closure and improving the nutritional status of patients requiring repeat operations. Moreover, other studies have shown that nutritional support decreases or modifies the composition of the GI tract secretions and is thus considered to have a primary therapeutic role in the management of fistula patients. Finally, if a fistula has not closed within 30 to 40 days, or if it is unlikely to close because of a variety of collateral or compounding pathophysiologic conditions, consideration must be given to operative resection of the fistula while continuing to maintain the previous nutritional and metabolic support. The morbidity and mortality rates in such unfortunate patients remain high despite the many recent advances in surgical and metabolic technology.