Background and Objective While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. Methods To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. Results Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. Conclusions Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.The members of "on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee" is present in the Acknowledgements section.

Objective: The objective of this article is to review the current supporting literature for the use of oral oncolytics in chronic lymphocytic leukemia, consideration for their use and management of adverse drug events that may limit use. Data Sources: NCCN guidelines were utilized to determine available oral options for treatment of chronic lymphocytic leukemia. A literature review was carried out through PubMed to find relevant clinical trials that evaluated the efficacy and safety of Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors and PI3K-δ inhibitors. Medication package inserts and primary literature regarding toxicity were used to determine appropriate adverse drug event management. Data Summary: A total of 7 clinical trials were found for the evaluation the efficacy and safety of burton tyrosine kinase inhibitor, 1 clinical trial for the BCL-1 inhibitor venetoclax and 4 trials were for PI3K-δ inhibitors. The data from these studies suggest that ibrutinib can be used first line in previously untreated patients and relapsed/refractory patients as well as acalabrutinib. The data also support the use of venetoclax, idelalisib, and duvelisib in relapsed/refractory chronic lymphocytic leukemia patients. Conclusions: The use of oral-only oncolytics could be a viable option for reducing the risk of infection due to limiting exposure to healthcare settings. Current literature suggests oral oncolytics may be an option, but there are several considerations to evaluate including medication adherence, drug-drug interactions, adverse events, and financial toxicity.

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IN a research, the primary object of which was an enquiry into the comparative activity of the ferments of the pancreas uinder different conditions, it was of importance to discover whether the pancreases of different animals exhibited any marked differenices in minute structure; in which case their histology might throw some light upon their function. With this object in view, therefore, the authors submitted to careful microscopical examination the paucreases of a considerable number of animals, and they have ventured in the present paper to bring together some of the notes upon the subject thinking that they may be of interest. They have done so with the knowledge that although the structure of the pancreas in its main features is sufficiently familiar to the histologist, few descriptions, except the most cursory, exist of one part of the gland structure, viz. the secondary groups of cells which are found among the glandular alveoli. The pancreases of the following animals have been minutely examined': man, monkey (several species), dog, cat, lion, leopard, serval, pig, bear, badger, fox, glutton, wallaby, weasel, potto, guinea-pig, otter, 1 We would take this opportunity of tendering our thanks to the Laboratories' Committee of the Royal Colleges of Physicians and Surgeons for their permission to work in the Colleges' Laboratories, and to the courteous Director, Dr Sims-Woodhead for his ever ready help.

tween the 32nd and 33rd. Just as it is conversely found that when the standard of graduation is made by dividing the interval between points marking respectively the temperature of the salt and ice mixture and of freezing water into 32, the mercury at blood heat stands at 98.40, and not at IooO.-I am, etc.