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Although children cannot be considered small adults due to nonlinear processes underlying the pharmacokinetics of drugs, pediatric doses are typically still expressed per kilogram. We use a physiologically based pharmacokinetic (PBPK) workflow to assess the accuracy of linear scaling of plasma clearance (CLp) for hypothetical drugs with ranges of realistic parameter values in pediatric patients of different ages. The results are compared with 0.75 fixed allometric scaling (AS 0.75). Linear CLp scaling is accurate down to the age of 1 month for drugs undergoing glomerular filtration, except when these drugs are highly bound to alpha-1-acid glycoprotein (AGP). For hepatically cleared drugs, linear scaling is reasonably accurate down the age of 2 years, except for AGP-bound drugs with a low extraction ratio and mature isoenzymes. In neonates, linear scaling outperforms AS 0.75 for human serum albumin (HSA) and AGP-bound drugs excreted through glomerular filtration. These results suggest that pediatric patients can, in many cases, be treated as small adults.

Parkinsons disease (PD) is a progressive neurodegenerative disease with substantial and growing socio‐economic burden. In this multifactorial disease, aging, environmental, and genetic factors contribute to neurodegeneration and dopamine (DA) deficiency in the brain. Treatments aimed at DA restoration provide symptomatic relief, however, no disease modifying treatments are available, and PD remains incurable to date. Mathematical modeling can help understand such complex multifactorial neurological diseases. We review mathematical modeling efforts in PD with a focus on mechanistic models of pathogenic processes. We consider models of α‐synuclein (Asyn) aggregation, feedbacks among Asyn, DA, and mitochondria and proteolytic systems, as well as pathology propagation through the brain. We hope that critical understanding of existing literature will pave the way to the development of quantitative systems pharmacology models to aid PD drug discovery and development.

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.

The consumption of asparagus is associated with the production of malodorous urine with considerable interindividual variability (IIV). To characterize the urinary odor kinetics after consumption of asparagus spears, we conducted a study with consenting attendees from two American Society for Clinical Pharmacology and Therapeutics (ASCPT) meetings. Subjects were randomized to eat a specific number of asparagus spears, and then asked to report their urinary odor perception. Eighty-seven subjects were included in the final analysis. A mixed effect proportional odds model was developed that adequately characterized the dose-response relationship. We estimated the half-life of the asparagus effect on malodorous urine to be 4.7 hours (relative standard error (RSE) = 13.2%), and identified a dose-response slope term with good precision (24.3%). Age was found as the predictor of IIV in slope estimates. This study design and tools can be used as a demonstration "crowdsourcing" project for studying population kinetics in organizational and educational settings.

Drug dosing regimen can significantly impact drug effect and, thus, the success of treatments. Nevertheless, trial and error is still the most commonly used method by conventional pharmacometric approaches to optimize dosing regimen. In this tutorial, we utilize four distinct classes of quantitative systems pharmacology models to introduce frequency-domain response analysis, a method widely used in electrical and control engineering that allows the analytical optimization of drug treatment regimen from the dynamics of the model.

To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside‐in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high‐throughput, low‐resource dose‐exposure‐effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery.

Welcome to the first issue of CPT: Pharmacometrics and Systems Pharmacology (CPT:PSP), a new journal from the American Society for Clinical Pharmacology and Therapeutics. CPT:PSP is a cross-disciplinary journal devoted to publishing advances in quantitative, model-based approaches as applied in pharmacology, (patho)physiology, and disease to aid the discovery, development, and utilization of human therapeutics. The emphasis of CPT:PSP will be on the application of modeling and simulation and the impact of Pharmacometrics and Systems Pharmacology on the discovery and development of innovative therapies.CPT: PharmacometricsSystems Pharmacology (2012) 1, e8; doi:10.1038/psp.2012.8; advance online publication 26 September 2012.