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Aims: We studied the pharmacokinetics and exposure–response relationships of the brentuximab vedotin (BV) antibody–drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. Methods: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. Results: BV ADC exhibited linear pharmacokinetics, well‐described by a three‐compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time‐varying formation rate. Simulated steady‐state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%–38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. Conclusions: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight‐based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted. [ABSTRACT FROM AUTHOR]

The article discusses the role of pharmacogenomics in pediatric oncology research and treatment, highlighting the importance of personalized medicine to optimize drug efficacy and minimize toxicity in children with cancer. It emphasizes the need for precision oncology and follow-up care strategies to improve outcomes and quality of life for pediatric cancer patients. The text also explores the impact of genetic variations on drug responses, such as in the case of methotrexate therapy for acute lymphoblastic leukemia, and the potential benefits of integrating pharmacogenomic knowledge into clinical practice. [Extracted from the article]

Background: This study aimed to investigate the pulmonary side effects of chemotherapy drugs in children with Acute Lymphocytic Leukemia (ALL) three years after treatment. The results could be of great help in managing lung complications in pediatric oncology patients. Materials and Methods: This cross-sectional descriptive study included 50 patients (22 males and 28 females) with ALL. Data were collected from patients' files, including age, sex, duration of illness, last dose of chemotherapy, and medications such as PEG.Asparginas, Cyclophosphamid, thioguanine, Dexamethason, cytarabin, cytosin.arabinosid, vincristine, mercaptopurine, and methotrexate. Pulmonary function tests (Forced Vital Capacity (FVC), FEV1 (Forced Expiratory Volume in the first second)) were assessed by spirometry. Results: Out of 50 patients, 47 (94%) did not have pulmonary disorders, while 3 (6%) had pulmonary dysfunction. Forty-seven patients (94%) did not have respiratory symptoms. FVC results showed that 45 patients were normal, and 5 were abnormal. Similarly, 45 patients had normal FEV1, and 5 had abnormal results. Spirometry results were normal in 45 patients and abnormal in 5. A significant relationship was found between the use of these drugs in different doses and spirometry results, recurrence rate, and pulmonary complications (P <0.05). No significant relationship was observed between pulmonary dysfunction and other drugs (P> 0.05). No correlation was found between pulmonary complications due to chemotherapy with duration of chemotherapy, patient age, and patient gender (P> 0.05). Conclusion: Pulmonary dysfunction and respiratory syndrome were observed in 6% of patients receiving chemotherapy. A significant relationship was found between the frequency of pulmonary and respiratory complications with some chemotherapy drugs in children with ALL. Further research is needed to optimize treatment strategies and minimize lung complications in pediatric oncology patients. [ABSTRACT FROM AUTHOR]

The widespread use of drugs for unapproved purposes remains common in children, primarily attributable to practical, ethical, and financial constraints associated with pediatric drug research. Pharmacometrics, the scientific discipline that involves the application of mathematical models to understand and quantify drug effects, holds promise in advancing pediatric pharmacotherapy by expediting drug development, extending applications, and personalizing dosing. In this review, we delineate the principles of pharmacometrics, and explore its clinical applications and prospects. The fundamental aspect of any pharmacometric analysis lies in the selection of appropriate methods for quantifying pharmacokinetics and pharmacodynamics. Population pharmacokinetic modeling is a data-driven method ('top-down' approach) to approximate population-level pharmacokinetic parameters, while identifying factors contributing to inter-individual variability. Model-informed precision dosing is increasingly used to leverage population pharmacokinetic models and patient data, to formulate individualized dosing recommendations. Physiologically based pharmacokinetic models integrate physicochemical drug properties with biological parameters ('bottom-up approach'), and is particularly valuable in situations with limited clinical data, such as early drug development, assessing drug–drug interactions, or adapting dosing for patients with specific comorbidities. The effective implementation of these complex models hinges on strong collaboration between clinicians and pharmacometricians, given the pivotal role of data availability. Promising advancements aimed at improving data availability encompass innovative techniques such as opportunistic sampling, minimally invasive sampling approaches, microdialysis, and in vitro investigations. Additionally, ongoing research efforts to enhance measurement instruments for evaluating pharmacodynamics responses, including biomarkers and clinical scoring systems, are expected to significantly bolster our capacity to understand drug effects in children. [ABSTRACT FROM AUTHOR]

The editorial in "Frontiers in Pharmacology" discusses recent advancements in perinatal and neonatal clinical pharmacology, emphasizing the importance of pharmaceutical interventions during the perinatal period. The complexity of drug therapy during pregnancy and neonatal care is highlighted, with a call for more research to establish optimal drug choices and dosing regimens. Various studies included in the research topic showcase different methodologies to understand drug effects in perinatal and neonatal pharmacology, emphasizing the need for a multifaceted approach and collaboration to improve health outcomes for these populations. [Extracted from the article]

Aims: The Medicines and Healthcare products Regulatory Agency Yellow Card scheme (YCS) is the UK's system that collects spontaneous reports about suspected adverse drug reactions (ADRs). Reporting of suspected ADRs by young people (age <19 years) in the UK is extremely uncommon, driving efforts to improve awareness and reporting. Methods: Quality improvement project, using an anonymous online survey about updated information for young people, distributed through school pupils (age 13–18 years) across the UK through the Alder Hey Research Ambassador programme. Results: Research Ambassadors were recruited in 21 schools and colleges, generating 2933 responses (15 November 2022–08 April 2023); 6.3% of respondents had heard of the YCS, and 0.8% had previously reported a Yellow Card. There were 307 suspected drug–event combinations reported, 36 of which required attendance at hospital. The updated YCS reporting guide was understood by 92.8% of young people, and 90.8% reported knowing more about ADRs after reading the guide. The percentage of young people 'Not comfortable' reporting a suspected ADR decreased from 13.3% (before reading) to 4.1% after reading (P <.000001), and 84.5% of young people reported willingness to report a side effect in the future. The most common comments regarding further improvement of the information were content, or length of the text could be altered in some way (n = 543, 26.1%) and graphic design could be improved (n = 357, 17.2%). Conclusions: The age‐appropriate information provided met many of their needs, increasing willingness to report. Integration into existing education curricula in the UK would facilitate knowledge transfer and improve reporting. [ABSTRACT FROM AUTHOR]

The knowledge about pharmacokinetics and dynamics of the drugs that will be administered in the pediatric population is of paramount importance, as they demand greater care according to their ontogenic characteristics and the low number of registered and tested drugs indicated for this population, causing high rates of intoxication and undesirable adverse effects. The present work carried out the analysis of prescriptions and medical records in the municipality of Jaguariúna-SP, in the Basic Health Unit to evaluate the drug indications according to the complaints of patients and/or guardians and clinical detections. It can be concluded the indiscriminate use of antibiotics, and for the most part vitamin and mineral supplements. Thus, demonstrating the importance of prescribing together with the pharmacist to promote the correct prescription, supporting the rational use of medicines, aiming at the health of children and adolescents. [ABSTRACT FROM AUTHOR]

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti‐infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti‐infective drugs. However, data from paediatric‐based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti‐infective drugs recommended for gene‐guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children. [ABSTRACT FROM AUTHOR]

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.

Majocchi’s granuloma is an invasive dermatophytosis that is rare in pediatric patients. The composite authors present a clinical case of Majocchi’s granuloma, which progressed under pressure of irrational external therapy of atopic dermatitis, which recovered under pressure of systemic therapy with fluconazole.

The current situation calls for careful planning of pediatric drug development as an integral part of the clinical development of drugs, particularly when the diseases for which the drug is being developed in adults also appear in children. "The pediatric drug development landscape today is vastly different from its unregulated beginnings" (Burckart and Kim [2]). Extent of safety database in pediatric drug development: Types of assessment, analytical precision, and pathway for extrapolation through on-target effects. The European Medicines Agency (EMA) and its Paediatric Committee (PDCO) reported in 2017 that more than 260 new medicines for use by pediatric patients have been authorized, with most of them linked to the Paediatric Regulation's requirements (Tomasi et al. [17]). [Extracted from the article]

Children with chronic diseases are prescribed various drugs by pediatricians. In children with chronic systemic disease, daily use of pediatric liquid form medications may be routine. Drugs such as analgesics, antibiotics, antihistamines, antiepileptics, multivitamins and antitussives are chronically prescribed to children. Sweeteners and sugars are added to make the flavors of the drugs prescribed by pediatricians in suspension forms acceptable to pediatric patients. The high sugars such as sucrose and glucose in the content of these drugs cause the dissolution of tooth enamel by lowering the pH of the dental biofilm as a result of bacterial fermentation. These drugs can cause tooth erosion due to their acidic properties and reducing saliva flow as a side effect. In addition to their corrosive and cariogenic properties, pediatric drugs also have side effects such as periodontal disease, changing orthodontic tooth movement, decreasing or increasing saliva flow, and causing tooth discoloration. Various recommendations can be made to parents, dentists and pharmaceutical companies in terms of preventive measures related to chronic drug use. In children with chronic drug use, rinsing the mouth with water after taking these drugs may not be enough to prevent tooth damage. Regular topical fluoride applications and the addition of calcium, fluoride or phosphate to drug formulations can be recommended for these patients as reduce the risk of dental caries and erosion. The aim of this review is to evaluate the effects of frequently used drugs on oral and dental health in pediatric patients based on current literature research. [ABSTRACT FROM AUTHOR]

The article discusses the knowledge gaps and challenges surrounding the use of medicines in children. It highlights the lack of medicines specifically labeled for pediatric use, leading to common off-label use. Efforts have been made to improve drug development for children, but the quality of evidence for pediatric pharmacotherapy still lags behind that for adults. The study mentioned in the article provides an overview of drug utilization in Swedish children, showing an increase in the average number of prescriptions and a significant proportion of off-label use. The article emphasizes the need for more research, clinical trials, and high-quality evidence to ensure children have access to safe and effective medicines. [Extracted from the article]

IntroductionModeling 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.MethodsAn 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.,

Purpose The anesthesiologist-directed sedation service has not been well established in Japan partly due to reimbursement issue. In this study, we compared the cost-effectiveness of sedation by non-anesthesiologists with that of sedation or general anesthesia by anesthesiologists under the Japanese medical fee schedule. Methods We conducted a single-center observational study with patients who required sedation or general anesthesia for magnetic resonance imaging (MRI) during a 12-month period. Costs per patient and failure rates of imaging were modeled in a decision analysis tree with sensitivity analysis. Costs were estimated from the health-care sector perspective. Results A total of 1546 patients were analyzed. The failure rate of sedation by non-anesthesiologists was 17.5% (264 out of 1506), whereas all the sedation and general anesthesia by anesthesiologists were successful. The cost-effectiveness analysis with setting successful sedation as outcomes showed that the mean cost per patient was 84.2 USD for sedation by anesthesiologists, followed by 74.2-92.7 USD for intravenous sedation by non-anesthesiologists, 112.1-458.3 USD for oral or rectal sedation by non-anesthesiologists, and 605.4 USD for general anesthesia by anesthesiologists. The one-way sensitivity analysis demonstrated that the cost per patient of sedation by a non-anesthesiologist would remain higher than that of sedation by an anesthesiologist, provided that the failure rate is over 11.3% for sedation via oral or rectal route, or over 3.6% for intravenous route, respectively. Conclusions Anesthesia-directed sedation would be more cost-effective than oral or rectal sedation by non-anesthesiologists for children undergoing MRI in the Japanese medical fee schedule., Author(s): Soichiro Obara [sup.1] [sup.2] [sup.3], Yoshinori Nakata [sup.1], Kazue Yamaoka [sup.1] Author Affiliations: (1) grid.264706.1, 0000 0000 9239 9995, Teikyo University Graduate School of Public Health, , 2-11-1 Kaga, [...]

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. [ABSTRACT FROM AUTHOR]

Maternal and pediatric populations have historically been considered "therapeutic orphans" due to their limited inclusion in clinical trials. Physiologic changes during pregnancy and lactation and growth and maturation of children alter pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Precision therapy in these populations requires knowledge of these effects. Efforts to enhance maternal and pediatric participation in clinical studies have increased over the past few decades. However, studies supporting precision therapeutics in these populations are often small and, in isolation, may have limited impact. Integration of data from various studies, for example through physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling or bioinformatics approaches, can augment the value of data from these studies, and help identify gaps in understanding. To catalyze research in maternal and pediatric precision therapeutics, the Obstetric and Pediatric Pharmacology and Therapeutics Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub. Herein, we provide an overview of the status of maternal–pediatric therapeutics research and introduce the Indiana University‐Ohio State University MPRINT Hub Data, Model, Knowledge and Research Coordination Center (DMKRCC), which aims to facilitate research in maternal and pediatric precision therapeutics through the integration and assessment of existing knowledge, supporting pharmacometrics and clinical trials design, development of new real‐world evidence resources, educational initiatives, and building collaborations among public and private partners, including other NICHD‐funded networks. By fostering use of existing data and resources, the DMKRCC will identify critical gaps in knowledge and support efforts to overcome these gaps to enhance maternal–pediatric precision therapeutics. [ABSTRACT FROM AUTHOR]

APPLICATION OF QSP MODELS IN DRUG DEVELOPMENT AND REGULATORY SUBMISSIONS QSP modeling and simulation is an approach that mechanistically and quantitively links molecular interactions of a drug candidate with complex human biology in normal or disease state. Quantitative systems pharmacology (QSP) models offer an opportunity to better understand the effects of drugs on pediatric growth and development and may be useful to guide pediatric-specific drug safety assessments. QSP models have been leveraged to support dose finding, dose selection, and dose optimization in drug development. [Extracted from the article]

This document is an editorial published in Frontiers in Pharmacology titled "Women in obstetric and pediatric pharmacology: 2023." The editorial addresses the global disparity in gender representation within the field of research, particularly in science, where less than 30% of researchers worldwide are women. It highlights the barriers and biases that women in science face, leading many talented female researchers to leave the scientific community. The editorial aims to showcase the contributions of female researchers in obstetric and pediatric pharmacology to address these inequities and promote the work of women scientists in the field. The document also includes summaries of several research studies on topics such as preeclampsia, hydroxychloroquine for preeclampsia treatment, ustekinumab use in pediatric Crohn's disease, and the relationship between preterm birth and postpartum depression. These studies emphasize the importance of understanding and addressing various health issues related to obstetric and pediatric pharmacology. [Extracted from the article]