Pharmacotherapy In Children Research Articles

Developmental Expression of Drug Transporters and Conjugating Enzymes Involved in Enterohepatic Recycling: Implication for Pediatric Drug Dosing.

Around 50% of the drugs used in children have never been tested for safety and efficacy in this vulnerable population. Immature drug elimination pathways can lead to drug toxicity when pediatric doses are determined using empirical methods such as body-surface area or body-weight-normalized adult dosing. In the absence of clinical data, physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to predict drug pharmacokinetics in children. These models utilize developmental physiological data, including age-dependent differences in the abundance of drug-metabolizing enzymes and transporters (DMET), to mechanistically extrapolate adult pharmacokinetic data to children. The reported abundance data of hepatic DMET proteins in subcellular fractions isolated from frozen tissue are prone to high technical variability. Therefore, we carried out the proteomics-based quantification of hepatic drug transporters and conjugating enzymes in 50 pediatric and 8 adult human hepatocyte samples. Out of the 34 studied proteins, 28 showed a significant increase or decrease with age. While MRP6, OAT7, and SULT1E1 were highest in < 1-year-old samples, the abundance of P-gp and UGT1A4 was negligible in < 1-year-old samples and increased significantly after 1 year of age. Incorporation of the age-dependent abundance data in PBPK models can help improve pediatric dose prediction, leading to safer drug pharmacotherapy in children.

Thrombopoietin receptor agonists in pharmacotherapy of pediatric immune thrombocytopenia

Introduction: Thrombopoietin receptor agonists are commonly second-line drugs in immune thrombocytopenia (ITP) pharmacotherapy in children and prescribed for chronic ITP refractory to first-line therapy.&#x0D; Standard ITP pharmacotherapy in children: includes prescribing glucocorticoids or intravenous immunoglobulins.&#x0D; Thrombopoietin receptor agonists: Currently Romiplostim and Eltrombopag are used in the Russian Federation pediatrics. Their pharmacodynamic features in comparison with other drugs used in ITP are presented in the paper. Increased thrombocytopoiesis is the dominant, but not the only component of Romiplostim and Eltrombopag mechanism of action. It is relevant to study their effect on immune tolerance in ITP, which may be associated with a persistent platelet response in some patients after drug discontinuation.&#x0D; Conclusion: The issue of thrombopoietin receptor agonist efficacy and safety as well as the mode of their use in ITP children treatment continues to be studied. The high cost of drugs continues to be a limiting factor to their earlier prescription. Generic drugs – Romiplostim and Eltrombopag partly solve the problem, promote their earlier prescription in ITP, but require additional study of their bioequivalence and therapeutic equivalence in comparison with the original drugs.&#x0D; Graphical Abstract&#x0D; &#x0D;

Real-world study: drug reduction in children with allergic rhinitis and asthma receiving immunotherapy.

Background: The reduction of pharmacological treatment after allergen immunotherapy (AIT)forhouse dust mites (HDMs) has been little studied in children. Objective: To evaluate the reduction of pharmacological treatment comparing children that receive HDM immunotherapy (AIT group) versus only pharmacotherapy. Methods: Ahistoric cohort of children with rhinitis or asthma was assessed. The main outcome was the frequency of complete drug discontinuation. Results: 100%drug reduction was higher for rhinitis (4-year cumulative incidence: 30vs 10.7%) and asthma (24.1vs 10.5%) in the AIT group (n=987) than in the pharmacotherapy group (n=2012). Conclusion: Immunotherapy is associated with a significant reduction of pharmacotherapy in children. This is a marker of clinical control and could be associated with positive economic impact.

Predictors of response to pharmacotherapy in children and adolescents with psychiatric disorders: A combined post hoc analysis of four clinical trial data.

The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR]=8.64, P < 0.001) and female sex (OR=1.89, P=0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR=3.47, P=0.009), as well as active drug use (OR=15.05, P < 0.001) and female sex (OR=2.87, P=0.016), were associated with subsequent responses. Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.

Sichere und passende Pharmakotherapie in der Kinderanästhesie

Safe and appropriate pharmacotherapy in children requires knowledge of age-group-specific features regarding pharmacology and drug dosing. In addition, aspects of medication safety must be considered. This review highlights basic principles and discusses key facts; further research in paediatric databases is recommended (www.kinderformularium.de).

How paediatric drug development and use could benefit from OMICs: A c4c expert group white paper.

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good-quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages.

3D printing of drugs: expanding the options for child-tailored pharmacotherapy

Lack of age-appropriate commercially available drugs hinders adequate pharmacotherapy in children. The European Union Paediatric Regulation (EC No1901/2006) and the establishment of the EU Paediatric Committee PDCO (2007) were aimed...

Efficacy of Weight Reduction on Pediatric Nonalcoholic Fatty Liver Disease: Opportunities to Improve Treatment Outcomes Through Pharmacotherapy.

Obesity is the single greatest risk factor for nonalcoholic fatty liver disease (NAFLD). Without intervention, most pediatric patients with NAFLD continue to gain excessive weight, making early, effective weight loss intervention key for disease treatment and prevention of NAFLD progression. Unfortunately, outside of a closely monitored research setting, which is not representative of the real world, lifestyle modification success for weight loss in children is low. Bariatric surgery, though effective, is invasive and can worsen NAFLD postoperatively. Thus, there is an evolving and underutilized role for pharmacotherapy in children, both for weight reduction and NAFLD management. In this perspective article, we provide an overview of the efficacy of weight reduction on pediatric NAFLD treatment, discuss the pros and cons of currently approved pharmacotherapy options, as well as drugs commonly used off-label for weight reduction in children and adolescents. We also highlight gaps in, and opportunities for, streamlining obesity trials to include NAFLD assessment as a valuable, secondary, therapeutic outcome measure, which may aid drug repurposing. Finally, we describe the already available, and emerging, minimally-invasive biomarkers of NAFLD that could offer a safe and convenient alternative to liver biopsy in pediatric obesity and NAFLD trials.

Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection.

Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected from 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100 to 400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets than with 50-mg tablets, while the extent of absorption remained unaffected. The identified Emax models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure led to marginal efficacy increase. Combination therapy should be considered, as a 12-fold-higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.

Pharmacotherapy in pediatric obesity: current evidence and landscape.

Childhood obesity is escalating globally. Lifestyle and behavioral changes, which are the frequently used interventions in clinical practice, lead to only modest improvements in children with established obesity. Bariatric surgery is currently the most effective obesity treatment but has very limited utilization in pediatric obesity and is preferentially used for children with worsening comorbidities. There exists a massive treatment gap for children suffering with obesity especially after the failure of lifestyle modifications. Pharmacotherapy that is an established management tool in adults is very infrequently used in children. Only two medications, Phentermine and Orlistat are approved by the Food and Drug Administration (FDA) for use in adolescent obesity. Herein, we discuss the current landscape and available literature on the use of antiobesity pharmacotherapy in children. There are emerging pediatric data about the efficacy of the many weight loss medications that are FDA approved in adults. Moreover, more clinical trials are underway on the rarer, intractable forms of obesity such as monogenic, syndromic, and hypothalamic obesity. Weight loss medications in children, like adults, have variable efficacy and similar side effect profiles. Rigorous research and improved education of providers about weight loss medications may address the huge treatment gap in severe pediatric obesity.

Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy.

The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable for use in pediatrics actively infected with TB. The formulation was prepared employing aqueous-particulate blending and solvent casting methods facilitated by a high performance Box Behnken experimental design template. The optimized orodispersible formulation was mechanically robust, flexible, easy to handle, exhibited rapid disintegration with initial matrix collapse occurring under 60 s (0.58 ± 0.05 min ≡ 34.98 ± 3.00 s) and pyrazinamide release was controlled by anomalous diffusion coupled with matrix disintegration and erosion mechanisms. It was microporous in nature, light weight (57.5 ± 0.5 mg) with an average diameter of 10.5 mm and uniformly distributed pyrazinamide load of 101.13 ± 2.03 %w/w. The formulation was physicochemically stable with no evidence of destructive drug–excipient interactions founded on outcomes of characterization and environmental stability investigations. Preliminary inquiries revealed that the orodispersible formulation was cytobiocompatible, palatable and remained intact under specific storage conditions. Summarily, an edible pyrazinamide containing orodispersible film formulation was optimally designed to potentially improve TB pharmacotherapy in children, particularly the under 5 year olds.

Manipulation of Medicinal Products for Oral Administration to Paediatric Patients at a German University Hospital: An Observational Study.

Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability of the manipulation of medicinal products before oral drug administration to paediatric inpatients in Germany. A prospective, direct observational approach was used. Two thousand and three medication preparation processes (MPP) in 193 patients were included in the analysis. Medicines were manipulated in 37% of oral administrations, affecting 57% of the patients. The percentage of manipulations was highest in infants/toddlers (42%) and lowest in adolescents (31%). Antiepileptics were most frequently manipulated (27%), followed by vitamins (20%) and drugs for acid-related disorders (13%). Fifty-six per cent of all manipulations were off-label. In 71% of these, no alternative appropriate medicinal product was commercially available. These results demonstrate that the manipulation of medicinal products before oral administration is common in paediatric wards in Germany. About half of the manipulations were off-label, indicating that no suitable formulation was available. Evidence-based guidelines for manipulations are required, with the overall aim of improving the safety of paediatric drug therapy.

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care. Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

Cough in children: issues of diagnosis and rational therapy

The presented review is devoted to topical issues of managing patients with cough, includes literature data on epidemiology, clinical classification, analysis of the causes, and the necessary diagnostic methods and lines of cough pharmacotherapy in children. The article focuses on the differential diagnosis of various pathological conditions and diseases, where cough is the leading clinical sign. The author provides information on treatment and characteristics of drugs recommended for symptomatic therapy of cough and indicates principles for rational antitussive and mucoactive pharmacotherapy.

Integrated ABC/VEN-analysis of medicinal prescribing in pharmacotherapy of bronchial asthma in children

Nowadays, medical institutions pay great attention to optimizing the medicine provision of inpatients. A significant range of medicines, which are registered in Ukraine and are used for the treatment of bronchial asthma (BA) in children, require improving the system of their selection for a particular department in conditions of optimal use of limited funds.Aim. The aim of the work is to assess the expense rationality of BA pharmacotherapy in children by the results of ABC/VEN-analysis.Materials and methods. Retrospective analysis of historical data of medical records in patients with the main diagnosis of BA, ABC/VEN-analysis.Results. For the economic evaluation of the rational medicine usage, an ABC-analysis was performed, which made it possible to rank medical prescriptions by level of consumption. Group A (80 % of costs) was formed by 14 international non-proprietary names (INN) (11.2 % of the total INN number), Group B (15 % of costs) – 25 INN (25.2 %), and Group C (5 % of the cost) – 61 INN (63.6 %). Formal VEN-analysis revealed the ratio of indices for INN, trade names and the number of medical prescriptions, which were 3:27:41; 11:74:102 and 411:768:618 respectively. It was established that during 2018 the largest part of group A expenditure was occupied by the segment of essential medicine (54.7 %), and vital – only 17.9 %, which indicates the need to further optimize the drug supply for children with asthma.Conclusions. The results of the conducted research demonstrate the need to improve the medicine provision of children with asthma, and can be used to make management decisions, purchase medicine by healthcare institutions and reduce the cost of pharmacotherapy by increasing the share of domestic medicine.

The frequency and VEN-analysis of pharmacotherapy in children with ARVI in the healthcare institution of the Poltava region

Acute respiratory viral infections (ARVI) are diseases that have important medico-social importance since they are associated with a wide distribution among the population, the risk of complications, reduced quality of life of patients, and high total cost of treatment. Aim. To assess the quality of pharmacotherapy: the frequency of prescribing drugs for children with ARVI in the health­care institution of the Poltava region and the correspondence of drug prescriptions to clinical protocols for providing medical care and the State Formulary of Medicines of Ukraine (SFMU). Materials and methods. The quality assessment of pharmacotherapy of children with ARVI was performed using auxiliary clinical and economic methods – the frequency and formal VEN-analyses. Results. The main directions of pharmacotherapy of children with ARVI in one of the healthcare institution of the Pol­tava region correspond to the unified clinical protocol of the primary care for adults and children with ARVI and clinical protocols for pharmacotherapy of concomitant diseases. Using the formal VEN-analysis it has been determined that the majority of INN drugs prescribed are recommended by clinical protocols for pharmacotherapy of the main (ARVI) and associated diseases registered in patients, and are available in the SFMU (87.50 and 54.69 %, respectively). Conclusions. The formal VEN analysis has shown that the ARVI pharmacotherapy correction is needed in the health­care institution of the Poltava region studied since a significant part of the INN drugs prescribed is absent in the SFMU (45.31 %) and in clinical protocols for the primary pharmacotherapy (ARVI) and associated diseases (17.19 %). In both medical and technological documents there are no 12.50 % of INNs prescribed. For them 11.74 % of funds (4808.81 UAH) were spent by parents of sick children; they were prescribed 8.74 % times (38 prescriptions) of the total number of prescriptions – 431.

Evaluation of the clinical efficacy of anti-asthma pharmacotherapy in children using the software package based on the Fishburn method

Aim: to assess the clinical efficacy of pharmacotherapy regimens using a software package. The article presents a method for assessing the clinical efficacy of pharmacotherapy regimens in children with exacerbation of bronchial asthma (BA); the method is based on comparing the treatment regimens by their significance using the Fishburn method. Materials and methods. We retrospectively analyzed the results of pharmacotherapy in 608 pediatric patients with BA treated in the hospital of Nizhny Novgorod in 2014-2015. We adopted the Fishburn method for determining the weights of each of the used regimens and their subsequent distribution by levels of clinical efficacy. The software was developed using high level C ++ language in the Borland Developer Studio 2006 environment. Results and discussion. The distribution included three levels (high, medium and low) and the subsequent clinical efficacy assessment – two levels (high and low). The high level (0.167-0.250) pertained to the combination of inhaled glucocorticosteroids (IGCS), short-acting β 2- agonists (SABA) and antagonists of leukotriene receptors (ALR), the combination of IGCS, long-acting β 2-agonists (LABA) and ALR, and the combination of IGCS and ALR. The average level (0.083-0.167) was given to the combination of SABA and ALR and the combination of IGCS and LABA. The low level (0-0,083) included the combination of IGCS and SABA and IGCS monotherapy. When classified by two levels of clinical efficacy, the following results were obtained: the high level (0.125-0.250) – the combination of IGCS, SABA and ALR, the combination of IGCS, LABA and ALR, the combination of IGCS and ALR, and the combination of SABA and ALR; the low level (0-0,125) – the combination of IGCS and LABA, the combination of IGCS and SABA, and IGCS monotherapy. The calculating algorithm for the software “Computer program for the distribution of drugs by levels of clinical efficacy” is presented. Conclusion. It has been shown that the combined anti-asthma therapies based on IGCS and ALR are characterized by a high level of clinical efficacy.

Levels of angiotensin peptides in healthy and cardiovascular/renal-diseased paediatric population-an investigative review.

The renin-angiotensin-aldosterone system (RAAS) plays a major role in the regulation of blood pressure and homeostasis. Therefore, it is a commonly used target for pharmacotherapy of cardiovascular diseases in adults. However, the efficacy of this pharmacotherapy can only be limitedly derived into children. Comprehensive knowledge of the humoral parameters acting in the paediatric RAAS (e.g. angiotensin I, angiotensin II, angiotensin 1-7, angiotensin III, and angiotensin IV) might facilitate a more effective and rational pharmacotherapy in children. Therefore, this review aims to provide an overview of the maturing RAAS. Out of 925 identified records, 35 publications were classified as relevant. Physiological and pathophysiological concentrations of angiotensin peptides were compiled and categorised according to European Medicines Agency age groups. Age has a major impact on circulating angiotensin I, angiotensin II, and angiotensin 1-7, which is reflected in an age-dependent decrease during childhood. In contrast to data obtained in adults, no gender-related differences in angiotensin levels were identified. The observed increase in peptide concentrations regarding cardiac- and renal-diseased children is influenced by surgical repair, while evidence for a pharmacological impact is conflicting. A comprehensive set of angiotensin I, angiotensin II, and angiotensin 1-7 values from neonates up to adolescents was compiled. Indicating age as a strong effector. However, evidence about potential promising targets of the RAAS like angiotensin III and angiotensin IV is still lacking in children.

Pharmacotherapy in Children and Adolescents: Oncology.

Pharmacotherapy in paediatric oncology is a difficult task. It is challenging to determine the optimal dose in children of different age groups. In addition, anticancer drugs display severe side effects reducing the quality of life. Late effects like secondary tumours and cardiotoxicity can be apparent years after treatment and must be taken into account when planning treatment schedules. Classical cytoreducing agents are still of great importance in treating children with leukaemia and solid tumours. In addition, drugs developed by rational drug design (targeted drugs) are a very important part of many treatment protocols, and newer drugs are emerging in several types of cancer. Unfortunately, there is only limited experience with newer drugs in children, because new drugs are mostly developed for adults. Complicated therapy regimens require a solid knowledge of the pharmacology of the drugs applied. This chapter attempts to introduce some pharmacological knowledge for the most important anticancer drugs in children with a focus on side effects and age-specific considerations.

Understanding the Effects of Kidney Disease and Dialysis Treatment on Pharmacotherapy in Children.

Chronic kidney disease (CKD) and acute kidney injury (AKI) requiring renal replacement therapy (RRT) by dialysis are rare conditions in pediatric patients. In pediatric patients with CKD, dialysis is mainly performed using peritoneal dialysis (PD) or intermittent hemodialysis (HD). In patients with AKI, continuous renal replacement therapy (CRRT) using hemofiltration, hemodialysis, or both techniques can be used. This chapter reviews (1) physiology and epidemiology of kidney disease and dialysis in children and (2) pharmacokinetic principles to be considered for developing pediatric dose recommendations under different dialysis modalities. Methods for both calculating and predicting dialysis drug clearance are reviewed; scaling approaches for predicting dialysis clearance in pediatric patients from data obtained in adults are discussed.