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1.  A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms 
The AAPS Journal  2013;15(4):1072-1081.
Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.
PMCID: PMC3787237  PMID: 23907486
children; drugs; formulations; manufacturing; palatability; pediatrics; regulatory
2.  Risk Assessment of Drug Interaction Potential and Concomitant Dosing Pattern on Targeted Toxicities in Pediatric Cancer Patients 
The AAPS Journal  2013;15(3):775-786.
This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children’s Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen–diphenhydramine occurred most frequently; however, methotrexate–vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (≤30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ≤30 min increasing the risk of hepatotoxicity with fentanyl–midazolam and methotrexate–midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity.
PMCID: PMC3691430  PMID: 23595361
drug interaction; pediatric oncology; pharmacotherapy; toxicity
3.  Strategic Biomarkers for Drug Development in Treating Rare Diseases and Diseases in Neonates and Infants 
The AAPS Journal  2013;15(2):447-454.
There are similar challenges in developing a product designed to treat patients with a rare disease and drugs to treat critically ill neonates and infants. Part of the challenge in developing such products as well as identifying the optimal dosing regimen for the treatment of young children arises from the complex interrelationship between developmental changes and changes in biomarkers responsive to drug therapy. These difficulties are further compounded by our lack of understanding of the key physiological factors that cause the differences in clinical responses between adults and neonates and infants. Regulatory efforts have succeeded in overcoming these challenges in many areas of pediatric and orphan drug development. Strategic applications of biomarkers and surrogate endpoints for the development and approval of a product used to treat an orphan disease will be highlighted with examples of approved products. Continued efforts are still needed to fill in our knowledge gap and to strategically link biomarkers and surrogate endpoints to clinical responses for rare diseases and diseases affecting neonates and infants.
PMCID: PMC3675740  PMID: 23334978
biomarkers; infants; neonates; rare diseases
4.  The Role of Quantitative Pharmacology in an Academic Translational Research Environment 
The AAPS Journal  2008;10(1):9-14.
Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury. Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies. While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative. The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research. A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships. The infrastructure of the University of Pennsylvania/Children’s Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology. A case study, NIH-sponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm.
PMCID: PMC2751447  PMID: 18446501
Model-based drug development; NIH Roadmap; Quantitative pharmacology; Translational research
5.  Population pharmacokinetic studies in pediatrics: Issues in design and analysis 
The AAPS Journal  2005;7(2):E475-E487.
The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.
PMCID: PMC2750985  PMID: 16353925
population pharmacokinetics; pediatrics; body size; sparse sampling; clinical trial simulation
6.  Modeling and simulation of adherence: Approaches and applications in therapeutics 
The AAPS Journal  2005;7(2):E390-E407.
Partial adherence with a prescribed or randomly assigned dose gives rise to unintended variability in actual drug exposure in clinical practice and during clinical trials. There are tremendous costs associated with incomplete and/or improper drug intake—to both individual patients and society as a whole. Methodology for quantifying the relation between adherence, exposure and drug response is an area of active research. Modeling and statistical approaches have been useful in evaluating the impact of adherence on therapeutics and in addressing the challenges of confounding and measurement error which arise in this context. This paper reviews quantitative approaches to using adherence information in improving therapeutics. It draws heavily on applications in the area of HIV pharmacology.
PMCID: PMC2750977  PMID: 16353919
adherence; modeling; simulation; PK/PD; NONMEM

Results 1-6 (6)