Clinical Pharmacology and Pharmacometrics to Better Understand Physiological Changes During Pregnancy and Neonatal Life.

Pregnant women, fetuses, and newborns are particularly vulnerable patient populations. During pregnancy, the body is subject to physiological changes that influence the pharmacokinetics and pharmacodynamics of drugs. Inappropriate dosing in pregnant women can result in sub-therapeutic or toxic effects, putting not only the pregnant woman but also her fetus at risk. During neonatal life, maturation processes also affect pharmacokinetics and pharmacodynamics of drugs. Inappropriate dosing in newborns leads not only to short-term complications but can also have a negative impact on the long-term development of infants and children. For these reasons, it is crucial to characterize physiological changes in pregnant women, describe placental transfer kinetics of drugs, and describe physiological changes related to the transition from intrauterine to extrauterine life and maturation processes in preterm and term neonates. Quantitative pharmacological approaches such as pharmacometric and physiologically-based modeling and model-based simulations can be useful to better understand and predict such physiological changes and their effects on drug exposure and response. This review article (1) gives an overview of physiological changes in pregnant women, their fetuses, and (pre)term neonates, (2) presents case studies to illustrate applications of new modeling and simulation approaches, and (3) discusses challenges and opportunities in optimizing and personalizing treatments during pregnancy and neonatal life.

Validation of a Dried Blood Spot Ceftriaxone Assay in Papua New Guinean Children with Severe Bacterial Infections.

Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study, we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children with severe illness from Papua New Guinea (PNG), a setting in which health care resources are limited and anemia is common. Using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5 to 10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models. Ten children were recruited with an admission hematocrit of 0.22 to 0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman's rank correlation coefficient [rs] = 0.94 [95% confidence interval, 0.91 to 0.97], P < 0.0001). A marked systematic hematocrit bias was observed, with lower hematocrits resulting in underestimation of DBS-predicted plasma concentration. After adjustment for red cell partitioning and hematocrit bias, a population PK model comparing plasma and DBS-predicted plasma concentrations did not differ in terms of key PK parameters, including clearance, volume of distribution, and residual variability. The performance of the ceftriaxone DBS assay is robust and provides reassurance that this platform can be used as a surrogate for plasma concentrations to provide valid PK and PK/pharmacodynamic studies of severely unwell children hospitalized in a resource-limited setting. It highlights the importance of hematocrit bias in validation studies of DBS assays.

Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection.

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or per os (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% did for Pseudomonas aeruginosa and 3% for Staphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).

Bupropion and Escitalopram During Lactation.

OBJECTIVE: To report a case of seizure-like symptoms in an infant exposed to bupropion and escitalopram through breastfeeding. CASE SUMMARY: A 6.5-month-old female infant, breastfed by a mother treated with bupropion XL 150 mg/d and escitalopram 10 mg/d for depression, presented to our hospital with severe emesis and tonic seizure-like symptoms. The symptoms resolved with supportive therapy. Urine toxicology screen in the infant revealed bupropion and escitalopram. Bupropion, and its active metabolite, hydroxybupropion, were analyzed and quantified both in the infant's serum and in the breast milk. Diagnostic workup for seizure etiologies was otherwise negative. After being asymptomatic for 48 hours, her discharge diagnosis was adverse events associated with bupropion and escitalopram in lactation. An objective causality assessment (Naranjo assessment) revealed that this adverse effect was probable. DISCUSSION: The adverse events in our case were associated with serum concentrations of bupropion and hydroxybupropion that are lower than the reported therapeutic range, perhaps suggesting that infants, compared with adults, may have a higher susceptibility to the epileptogenic effects of bupropion and/or hydroxybupropion. Furthermore, although we do not have escitalopram serum concentrations, this drug interaction may have had a contributing role in this case, possibly because of cytochrome P4502D6 inhibition by bupropion and metabolites. CONCLUSION: As the number of reproductive-aged women requiring polytherapy to control their depression is increasing, further research is needed to establish the safety of combined antidepressants, such as selective serotonin reuptake inhibitors and bupropion, during lactation.

Dose optimization and target attainment of vancomycin in children.

Vancomycin is a glycopeptide antibiotic that has been adopted in clinical practice to treat gram-positive infections for more than 70 years. Despite vancomycin's long history of therapeutic use, optimal dose adjustments and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in children are still under debate. Therapeutic drug monitoring (TDM) has been widely integrated into pediatric clinical practice to maximize efficacy and safety of vancomycin treatment. Area under the curve (AUC)-guided TDM has been recently recommended instead of trough-only TDM to ensure PK/PD target attainment of AUC0-24h/minimal inhibitory concentration (MIC) > 400 to 600 and minimize acute kidney injury risk. Bayesian forecasting in pediatric patients allows estimation of population PK to accurately predict individual vancomycin concentrations over time, and consequently total vancomycin exposure. AUC-guided TDM for vancomycin, preferably with Bayesian forecasting, is therefore suggested for all pediatric age groups and special pediatric populations. In this review we aim to analyze the current literature on the pediatric use of vancomycin and summarize the current knowledge on dosing optimization for target attainment in special patient populations.

Postoperative Analgesia With Modified Thoracoabdominal Nerve Block Through Perichondrial Approach in Neonatal and Infantile Abdominal Surgery.

Modified thoracoabdominal nerve block through the perichondrial approach (M-TAPA) is a novel strategy for peripheral nerve block in the abdomen. Its usefulness has been highlighted in adults, but no literature is currently available regarding its efficacy in infants. This report describes the cases of a one-day-old neonate in open abdominal surgery and a one-month-old infant in laparoscopic surgery who received M-TAPA. The postoperative condition of the infants was assessed through a neonate pain scale and the Face, Legs, Activity, Cry, and Consolability behavioral scale, respectively; both scales remained at 0 until discharge. Despite the need for special attention, M-TAPA may provide effective analgesia in neonatal and infant abdominal surgery in addition to adult cases, and its indications should be considered.

Alternative Treatments to Pharmacological Therapy in Pediatric Populations With Attention-Deficit/Hyperactivity Disorder (ADHD): A Scoping Review.

In recent years, there has been an increase in the prevalence of the diagnosis of attention-deficit/hyperactivity disorder (ADHD), a cognitive and behavioral disorder in which individuals present with inattention and impulsivity, in the pediatric population. With an increase in diagnoses, there is also increasing concern regarding overdiagnosis and overtreatment with medications for ADHD. The objective of this study was to map out and compile the recent literature pertaining to alternative therapies (e.g., physical activity, diet, mindfulness, and computer-based interventions) for children and adolescents diagnosed with ADHD in an attempt to reduce or replace the use of pharmacological therapy. This scoping review searched articles from multiple databases (PubMed, ScienceDirect, Web of Science, Directory of Open Access Journals, Scopus, and CINAHL). Using search terms "children with ADHD," "alternative treatment," and "cognitive behavioral therapy," articles were identified that were specific to the research question. The inclusion criteria were patients under the age of 18 with a previous diagnosis of ADHD, no other comorbid illnesses, alternative treatments, and was limited to studies published between 2012 and 2022. After removing duplicates, screening for eligibility criteria, and conducting a critical appraisal of the articles, 16 articles were retained for the final review. The main alternative therapeutic domains that emerged were (1) physical activity, (2) diet, (3) mindfulness, (4) computer-based interventions, and (5) miscellaneous interventions. Seven articles assessed the effect of physical activity on executive and cognitive function in children and adolescents with ADHD. Most findings showed improvement with increased physical activity. Two articles explored the effect of diet on the improvement of ADHD symptoms and reported a positive impact. The two articles that evaluated the effects of mindfulness on ADHD symptoms reported a reduction in ADHD symptoms. Two studies evaluated the use of computer-based interventions as an adjunct treatment in children and adolescents with ADHD; improvements in symptoms were reported. One study each evaluated interventions based on music and nerve stimulation. These showed an improvement in attention, memory, and executive function. With the increasing prevalence of ADHD diagnosis in children and adolescents, alternative and/or adjunctive treatments may be a viable and valuable alternative to pharmaceutical interventions. The findings from this review suggest that multiple non-pharmacological interventions effectively reduce symptoms of ADHD in children and adolescents, including diet, exercise, mindfulness, computer-based interventions, music, and nerve stimulation. While there are implications for alternatives to be used in the future, more research is warranted using larger samples with controlled trials.

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept.

Introduction: Modeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation. Methods: An already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios. After acceptance of the model, dosages now recommended by the Dutch Pediatric Formulary (DPF) were simulated, along with several alternative dosing scenarios, aiming for recommended peak (i.e., 8-12 mg/L for neonates and 15-20 mg/L for infants) and trough (i.e., <1 mg/L) levels. We then used a decision framework to weigh benefits and risks for implementation. Results: The PBPK model adequately described gentamicin PK. Simulations of current DPF dosages showed that the dosing interval for term neonates up to 6 weeks of age should be extended to 36-48 h to reach trough levels <1 mg/L. For infants, a 7.5 mg/kg/24 h dose will reach adequate peak levels. The benefits of these dose adaptations outweigh remaining uncertainties which can be minimized by routine drug monitoring. Conclusion: We used a PBPK model to show that current DPF dosages for gentamicin in term neonates and infants needed to be optimized. In the context of potential uncertainties, the risk-benefit analysis proved positive; the model-informed dose is ready for clinical implementation.

Optimizing Vancomycin Therapy in Critically Ill Children: A Population Pharmacokinetics Study to Inform Vancomycin Area under the Curve Estimation Using Novel Biomarkers.

Area under the curve (AUC)-directed vancomycin therapy is recommended, but Bayesian AUC estimation in critically ill children is difficult due to inadequate methods for estimating kidney function. We prospectively enrolled 50 critically ill children receiving IV vancomycin for suspected infection and divided them into model training (n = 30) and testing (n = 20) groups. We performed nonparametric population PK modeling in the training group using Pmetrics, evaluating novel urinary and plasma kidney biomarkers as covariates on vancomycin clearance. In this group, a two-compartment model best described the data. During covariate testing, cystatin C-based estimated glomerular filtration rate (eGFR) and urinary neutrophil gelatinase-associated lipocalin (NGAL; full model) improved model likelihood when included as covariates on clearance. We then used multiple-model optimization to define the optimal sampling times to estimate AUC24 for each subject in the model testing group and compared the Bayesian posterior AUC24 to AUC24 calculated using noncompartmental analysis from all measured concentrations for each subject. Our full model provided accurate and precise estimates of vancomycin AUC (bias 2.3%, imprecision 6.2%). However, AUC prediction was similar when using reduced models with only cystatin C-based eGFR (bias 1.8%, imprecision 7.0%) or creatinine-based eGFR (bias -2.4%, imprecision 6.2%) as covariates on clearance. All three model(s) facilitated accurate and precise estimation of vancomycin AUC in critically ill children.

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children.

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.

Establishing evidence-based pharmacologic treatments for neonatal abstinence syndrome: A retrospective case study.

Translation of research discoveries into health impact can take many years, creating delays in improving clinical outcomes. One approach to promoting timely translation is to examine successful cases in order to understand facilitators and strategies for overcoming barriers. We examined the development of evidence-based management for neonatal abstinence syndrome (NAS) at one academic medical center, with a primary focus on pharmacologic treatment. Despite a substantial increase in NAS case incidence starting in the early 2000s, significant sociocultural, policy, and regulatory barriers limited collaborative NAS research. Facilitators for translation encompassed: 1) pursuing research of societal interest, 2) building an effective interdisciplinary team, 3) intentionally linking clinical, research, and advocacy efforts, 4) broad stakeholder engagement across clinical, policy, and research arenas, and 5) leveraging local resources. Challenges included lack of commercially available U.S. Food and Drug Administration approved neonatal drug formulations, legal and regulatory barriers related to off-label and illicit use of opioids, recruitment for a treatment associated with drug withdrawal syndromes, misalignment of research design needs with real-world scenarios, and episodic funding. Benefits of successful translation included improvements in clinical care, reduced healthcare costs related to NAS, and enhanced legislative, policy, and research strategies to support broader neonatal investigations.

Population pharmacokinetics of mycophenolate mofetil in pediatric patients early after liver transplantation.

Objective: To investigate the factors influencing the pharmacokinetics of mycophenolate mofetil (MMF) in pediatric patients after liver transplantation, and to establish a population pharmacokinetics model, which can provide a reference for clinical dosage adjustment. Methods: A prospective study in a single center was performed on pediatric patients who were administrated with mycophenolate mofetil dispersible tablets (MMFdt) for at least 4 days after liver transplantation continuously. Blood samples were collected in ethylene diamine tetraacetic acid anticoagulant tubes before dosing and 0.5, 1, 2, 4, 8, and 12 h after the morning intake of MMFdt. The concentrations of mycophenolic acid (MPA) in plasma were assayed with a validated reverse-phase high-performance liquid chromatography method. UGT1A8 518C > G, UGT1A9 -275T > A, UGT1A9 -2152C > T, UGT2B7 211G > T, SLC O 1B1 521T > C polymorphism were determined by Sanger sequencing. Nonlinear mixed effects modeling was used to establish the population pharmacokinetics (PPK) model. The predictability and stability of the model were internally evaluated by the goodness of fit plots, visual prediction check, normalized prediction errors, and bootstraps. Results: A two-compartment model with first-order absorption and first-order elimination was established with 115 MPA concentrations from 20 pediatric patients. The final model were: CL/F (L/h) = 14.8×(WT/7.5)0.75×(DOSE/11.16)0.452×е0.06, Ka (h-1) = 2.02×(WT/7.5)-0.25, Vc/F (L) = 6.01×(WT/7.5), Vp/F (L) = 269 (fixed), Q/F (L/h) = 15.4×(WT/7.5)0.75×е1.39. Where CL/F was the apparent clearance rate, Ka was the absorption rate constant, Vc/F was the apparent distribution volume of the central compartment, Vp/F was the apparent distribution volume of the peripheral compartment, Q/F was the atrioventricular clearance rate, WT was the body weight of the subject, and DOSE was the MMFdt administered dose. The model indicated there was large inter-individual variability in CL/F and Q/F after multiple dosing of MMFdt. Internal evaluation results showed that the final model had good stability and prediction performance. Conclusion: A stable and predictive population pharmacokinetic model of MMFdt in pediatric patients after the early stage of liver transplantation was established. The pediatric patient's weight and the dose of MMFdt can be a reference to adjust the MMFdt dose.

Pharmacogenetic Analysis of Voriconazole Treatment in Children.

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections.

Knowledge, Attitude, and Practice of Paracetamol and Ibuprofen Administration Among Caregivers of the Pediatric Age Group in Jeddah.

Background Fever is one of the most common pediatric conditions usually managed by parents and the cause of nearly all pediatrician visits. However, many parents find the management of childhood fever and febrile diseases challenging owing to a lack of understanding of the nature, effects, and therapies of fever management. Objectives This study aimed to assess the knowledge, attitude, and practice of paracetamol and ibuprofen administration among caregivers of the pediatric age group. Design Observational cross-sectional survey. Setting Jeddah, Saudi Arabia. Materials and Methods Data were collected between April 2018 and April 2019 using a pretested interviewer-administered questionnaire consisting of 40 questions. Sample Size Overall, 493 caregivers were interviewed. Results Paracetamol was reported as the most common antipyretic used by the caregivers (54%) to control fever. Ibuprofen was the least preferred drug (18.5%). The majority of the participants (51.7%) admitted administering antipyretics at a body temperature of 38-38.5°C. A total of 90.7% of the participants measured children's temperature using a thermometer before administering antipyretics. Dosage was determined according to each child's age (40.4%), weight (32%), or illness severity (27.6%). However, 36.7% and 51.5% of the participants were unsure of the correct dosage of paracetamol and ibuprofen, respectively. Regarding the maximum frequency of paracetamol use, only 3.7% of the participants answered correctly. Most parents (70.4%) believed that a paracetamol/ibuprofen prescription was not necessary. Overall, 97% of the sample demonstrated inadequate knowledge about antipyretic administration. Conclusions Most caregivers had inadequate knowledge regarding factors that influence paracetamol and ibuprofen dosage and frequency of administration. This low level of knowledge increases the risk of improper drug intake, which can result in serious side effects, thereby indicating the need for the development of educational route programs to provide parents with appropriate education and information on fever and fever management.

Ontogeny of Drug-Metabolizing Enzymes.

Almost 50% of prescription drugs lack age-appropriate dosing guidelines and therefore are used "off-label." Only ~10% drugs prescribed to neonates and infants have been studied for safety or efficacy. Immaturity of drug metabolism in children is often associated with drug toxicity. This chapter summarizes data on the ontogeny of major human metabolizing enzymes involved in oxidation, reduction, hydrolysis, and conjugation of drugs. The ontogeny data of individual drug-metabolizing enzymes are important for accurate prediction of drug pharmacokinetics and toxicity in children. This information is critical for designing clinical studies to appropriately test pharmacological hypotheses and develop safer pediatric drugs, and to replace the long-standing practice of body weight- or surface area-normalized drug dosing. The application of ontogeny data in physiologically based pharmacokinetic model and regulatory submission are discussed.

Potential implications of DMET ontogeny on the disposition of commonly prescribed drugs in neonatal and pediatric intensive care units.

Introduction: Pediatric patients, especially neonates and infants, are more susceptible to adverse drug events as compared to adults. In particular, immature small molecule drug metabolism and excretion can result in higher incidences of pediatric toxicity than adults if the pediatric dose is not adjusted.Area covered: We reviewed the top 29 small molecule drugs prescribed in neonatal and pediatric intensive care units and compiled the mechanisms of their metabolism and excretion. The ontogeny of Phase I and II drug metabolizing enzymes and transporters (DMETs), particularly relevant to these drugs, are summarized. The potential effects of DMET ontogeny on the metabolism and excretion of the top pediatric drugs were predicted. The current regulatory requirements and recommendations regarding safe and effective use of drugs in children are discussed. A few representative examples of the use of ontogeny-informed physiologically based pharmacokinetic (PBPK) models are highlighted.Expert opinion: Empirical prediction of pediatric drug dosing based on body weight or body-surface area from the adult parameters can be inaccurate because DMETs are not mature in children and the age-dependent maturation of these proteins is different. Ontogeny-informed-PBPK modeling provides a better alternative to predict the pharmacokinetics of drugs in children.

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development.

Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.

The Revolution in Pediatric Drug Development and Drug Use: Therapeutic Orphans No More.

This lecture was given by Dr. Burckart in association with presentation of the 2014 Sumner J. Yaffe Lifetime Achievement Award in Pediatric Pharmacology and Therapeutics, which is selected by the Pediatric Pharmacy Association. Multiple factors make conducting drug studies in the pediatric population difficult, resulting in a historic lack of information surrounding safe and efficacious drug dosing in children. The paradigm in pediatric drug development has shifted from normal science being that children are therapeutic orphans in the drug development system, to a model drift caused by pediatric legislation, to a model crisis caused by failed pediatric drug development trials, to finally a model revolution that includes pediatric patients routinely in drug development. Major regulatory actions and the accumulation of scientific evidence has created an environment where clinicians can expect properly labeled drug usage information for the pediatric population.