Pharmacokinetics Of Drugs 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.

Sex and Age Differences in the Pharmacokinetics of Drugs for Children with Chronic Kidney Disease: A Narrative Review

Title Sex Differences in the Pharmacokinetics of Drugs for Children with Chronic Kidney Disease: A Narrative Review Effective optimal pharmacotherapy requires a comprehensive understanding of the drug’s pharmacokinetic properties. Chronic kidney disease (CKD) influences medication pharmacokinetics. However, whether sex differences exist in the pharmacokinetics of drugs for children with CKD is unknown. The primary aim of this article was to evaluate the effect of sex on pharmacokinetics of drugs commonly used for CKD treatment in children. Secondary outcome was to address the impact of sex in CKD disease progression. Electronic databases, PubMed, EMBASE, Google Scholar, and Web of Science were searched from inception, using Mesh terms in English for sex differences in the pharmacokinetics of drugs in children with CKD. No studies have documented sex-related differences in the pharmacokinetics of drugs for the treatment of CKD in children. As a consequence, it is difficult to predict the effect of sex on pharmacokinetics by extrapolating data from adult studies to children. Evidence to date suggests that girls generally have a higher prevalence and disease progression of CKD when compared to boys regardless of age. Understanding the pharmacokinetics and pharmacodynamics of drugs provides practical consideration for dosing optimal medication regimens. Future kinetic studies are needed evaluating the effect of sex on the pharmacokinetics and pharmacodynamics of drugs in children with CKD. Keywords Children; Chronic kidney disease; Pharmacotherapy; Pharmacokinetics; Sex differences

Children and TB pharmacokinetics: no longer in infancy?

The comprehensive report from Gafar et al. [1] in this issue of the European Respiratory Journal provides the first systematic assessment of antituberculosis drug pharmacokinetics in children and adolescents to date. The authors have admirably collected and analysed the available information on this important topic, which also provides an opportunity for considering the gaps which still remain in our understanding and practice. While this approach to synthesis using an individual patient meta-analysis is an important contribution from this team, it is also reflective of the collective efforts of a significant number of smaller and carefully conducted studies over a 25-year period, each with groups willing to curate and share necessary data. This work, then, highlights a wider community of researchers, patients and families who have helped to build a platform on which better treatment can be developed and delivered. Accumulating evidence on TB pharmacokinetics in children and adolescents will be useful for improving outcomes and individualising therapy in future http://bit.ly/3E6hWSP

The association between enteropathogens and antimycobacterial drug pharmacokinetics in children

There were an estimated 1·09 million incident tuberculosis cases resulting in 226 000 deaths in children globally in 2020.1 The COVID-19 pandemic is reversing recent progress, meaning tuberculosis remains a major public health problem in children.1,2 First-line tuberculosis treatment relies on rifampicin, isoniazid, pyrazinamide, and ethambutol.3 In response to evidence of low exposures to first-line tuberculosis drugs in children, WHO recommended paediatric doses of rifampicin, isoniazid, and pyrazinamide were increased in 2010;3 however, even with the recommended higher doses, studies continue to demonstrate low exposures to these drugs in children, especially for the crucial drug rifampicin.

Pediatric Physiologically Based Pharmacokinetic Model Development: Current Status and Challenges

This article provides a brief overview of the development of pediatric physiologically based pharmacokinetic (PPBPK) models, the challenges of uncertain systems information, and finally performance verification considering recent regulatory guidance. Pediatric PBPK (PPBPK) model can incorporate varied manifolds of drug and developmental system information to predict drug PK in children. Health authorities have been receiving a growing number of drug submissions that have used PPBPK. According to a recent review of the FDA office of Clinical Pharmacology, PPBPK modeling has been readily applied for dose regimen selection in a variety of pediatric patient groups via a “learn and confirm” approach. Before applying to pediatrics, a PBPK model is developed using physicochemical, biopharmaceutical, and metabolic parameters of drug and then verified by pharmacokinetics (PK) data in adults. Once the drug parameters are optimized, they can be used in the PPBPK model which contains the ‘systemic’ data of physiology and biochemistry in children. The drug absorption, distribution, metabolism, and excretion (ADME) parameters can be estimated according to developmental changes in physiology and biochemistry in various age groups of children. The model is then applied to simulate the exposure in children. The current challenge is the paucity of available pediatric systems information and oral biopharmaceutics. They are essential to verify PPBPK models and predict PK particularly in neonates and young infants. The recent research on intestinal and hepatic transporter ontogeny, via mRNA and proteomic data, gives us increased understanding of pediatric drug absorption, hepatic uptake, and biliary excretion. Nevertheless, more validated developmental ‘system’ data is needed in this field. Another gap is the lack of good quality pediatric drug studies performed across the age range, which currently is a limitation to the performance verification of PPBPK models. PPBPK models have already improved the pediatric drug development process but the important challenges lie ahead. Further development and verification are constantly required. It may be possible to minimize the number of pediatric subjects used in PK studies and avoid some studies altogether.

The Ontogeny of UDP-glucuronosyltransferase Enzymes, Recommendations for Future Profiling Studies and Application Through Physiologically Based Pharmacokinetic Modelling.

Limited understanding of drug pharmacokinetics in children is one of the major challenges in paediatric drug development. This is most critical in neonates and infants owing to rapid changes in physiological functions, especially in the activity of drug-metabolising enzymes. Paediatric physiologically based pharmacokinetic models that integrate ontogeny functions for cytochrome P450 enzymes have aided our understanding of drug exposure in children, including those under the age of 2years. Paediatric physiologically based pharmacokinetic models have consequently been recognised by the European Medicines Agency and the US Food and Drug Administration as innovative tools in paediatric drug development and regulatory decision making. However, little is currently known about age-related changes in UDP-glucuronosyltransferase-mediated metabolism, which represents the most important conjugation reaction for xenobiotics. Therefore, the objective of the review was to conduct a thorough literature survey to summarise our current understanding of age-related changes in UDP-glucuronosyltransferases as well as associated clinical and experimental sources of variance. Our findings indicate that there are distinct differences in UDP-glucuronosyltransferase expression and activity between isoforms for different age groups. In addition, there is substantial variability between individuals and laboratories reported for human liver microsomes, which results in part from a lack of standardised experimental conditions. Therefore, we provide a number of best practice recommendations for experimental conditions, which ultimately may help improve the quality of data used for quantitative clinical pharmacology approaches, and thus for safe and effective pharmacotherapy in children.

Nanotechnology-Based Approaches in Pediatric Parasitic Infections

AbstractNanotechnology is getting more importance in pharmaceutical chemistry and has a significant role in enabling the drugs in targeting specific cells and tissues. Dose administration and formulation of drugs for pediatric patients remain a challenge; an ideal pediatric formulation must be in an appropriate dosage form that can be handled by the pediatric patients. Drug pharmacokinetics in children differs from the adults and also differs in toxicity and side effects. Therefore, treatment of diseases in pediatric patients cannot be simplified just to adjust the body weight or using measures such as cutting pills in half. In this regard, application of innovative techniques such as nanotechnology in the pediatric population is receiving enormous attention. This study discussed the application of nanotechnology for the treatment of malaria, leishmaniasis, toxoplasmosis, and schistosomiasis in pediatric patients.

Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in Indian children.

BackgroundThe available pharmacokinetic data on anti-tubercular drugs in children raises the concern of suboptimal plasma concentrations attained when doses extrapolated from adult studies are used. Also, there is lack of consensus regarding the effect of malnutrition on pharmacokinetics of anti-tubercular drugs in children. We conducted this study with the aims of determining the plasma concentrations of isoniazid, rifampicin, pyrazinamide and ethambutol achieved with different dosage of the anti-tubercular drugs so as to provide supportive evidence to the revised dosages and to evaluate the effects of malnutrition on the pharmacokinetics of these drugs in children. We also attempted to correlate the plasma concentrations of these drugs with clinical outcome of therapy.MethodProspective drug estimation study was conducted in two groups of children, age 6 months to 15 years, with tuberculosis, with or without severe malnutrition, receiving different dosage of daily anti- tubercular therapy. The dosage (range) of isoniazid was 5 (4-6) and 10 (7-15) mg/kg in the two groups, respectively, that of rifampicin-10 (8–12) and 15 (10–12) mg/kg, respectively, both the groups received same dose of pyrazinamide (30–35 mg/kg) and ethambutol (20–25 mg/kg). All four drugs were simultaneously estimated by liquid chromatography-mass spectrometry (LC-MS/MS).Results and conclusionThe median (IQR) Cmax of isoniazid increased significantly from 0.6 (0.3,1.2) μg/mL to 3.4 (1.8, 5.0) μg/mL with increase in the dose. Plasma rifampicin concentrations increased only marginally on increasing the dose [median (IQR) Cmax: 10.4 (7.2, 13.9) μg/mL vs. 12.0 (6.1, 24.3) μg/mL, p = 0.08]. For ethambutol, 55.9% of the children had inadequate 2-hour concentrations. Two-hour plasma concentrations of at least one drug were low in 59 (92.2%) and 54 (85.7%) children in the two dosing regimen, respectively. We did not observe any effect of malnutrition on pharmacokinetic parameters of the drugs studied. We did not observe an association between low plasma drug concentrations and poor outcome. We may have to be cautious while increasing the doses and strive to asses other factors influencing the drug concentrations and treatment outcomes in children.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-0862-7) contains supplementary material, which is available to authorized users.

Current Research Issues in the Pharmacokinetics of Antiretroviral Drugs in Children

Current Research Issues in the Pharmacokinetics of Antiretroviral Drugs in Children

The pharmacokinetic evaluation of artemisinin drugs for the treatment of malaria in paediatric populations

Introduction: The use of artemisinin combination therapies to treat uncomplicated malaria is growing and, therefore, so is the number of children exposed to these agents. As a result, there is a huge drive to develop paediatric formulations. However, relatively limited data exist regarding the pharmacokinetic properties of these drugs in this vulnerable population.Areas covered: The article reviews the pharmacokinetic data for artemisinin drugs used for the treatment of malaria in paediatric populations. The authors discuss how developmental and environmental factors can produce significant variation in the pharmacokinetic properties of artemisinin drugs. The authors also discuss how this variation may lead to suboptimal therapeutic drug concentrations with implications on efficacy, safety and the development of parasite resistance to these drugs.Expert opinion: There is currently a lack of published studies on the pharmacokinetics of artemisinin drugs in children and this subject is complicated by several interdependent variables. Therefore, the construction of a systems-based model of this subject should be a priority area in order to identify gaps in current knowledge to ensure their continued effective and safe use.

Pharmacokinetics of Anti-tuberculosis Drugs in Children

Tuberculosis (TB) is among the top 10 causes of death among children worldwide. Recent reports suggest that the currently recommended dosages of first-line anti-TB drugs are not adequate in children, particularly younger children. The objective of this review was to synthesize available pharmacokinetic data of anti-TB drugs in children from different settings that would help determine optimal doses of anti-TB drugs, in order to provide evidence-based recommendations. A PubMed database was searched from 1970 to present using the terms rifampicin, isoniazid, pyrazinamide, ethambutol, pharmacokinetics, HIV, TB, nutrition and children. References from identified articles were also reviewed and abstract from recent meetings were included. Available pharmacokinetic data from different settings suggest that age, nutritional status, HIV infection and gene polymorphisms in drug metabolising enzymes could significantly influence the pharmacokinetics of first-line anti-TB drugs. However, most of the pharmacokinetic studies conducted so far in children have failed to associate drug concentrations with treatment outcomes. Hence, more studies to examine the relationship between drug pharmacokinetics and response to anti-TB treatment are required. Studies to examine the impact of nutritional status and HIV infection on the pharmacokinetics of anti-TB drugs in children are needed.

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

protein energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics. literature searches in the MEDLINE and EMBASE databases (January 1960 to December 2009) were performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite-stimulating drugs. altogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was, however, unaffected for most of the drugs. The effect of PEM on total clearance and the half-life of drugs primarily metabolised by the liver was studied for 8 drugs. There was decreased total clearance and an associated increased half-life of 5 drugs. For 2 drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs, but significantly decreased for two drugs (cefoxitin and penicillin). considering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.

The trials and tribulations of pediatric drug trials

Children are not little adults. This oft-repeated mantra implies that to study the safety and efficacy as well as the pharmacokinetics of drugs in children, it is not sufficient to simply extrapolate adult data. This is the position of the American Academy of Pediatrics. Moreover, the Food and Drug Administration (FDA) grants approval for drugs based on the populations in which they were studied. In partial seizures in older children, one can usually presume that drugs effective in adults with partial seizures will also be effective in children, although the safety and pharmacokinetics will be different as noted in a National Institute of Neurologic Disorders and Stroke consensus conference on the development of new antiepileptic drugs (AEDs) in children.1 In neonates and infants, no such assumptions can be made.1,2 Yet despite financial incentives to pharmaceutical manufacturers in the form of additional patent exclusivity period on a product, there are few drugs (and in particular, few AEDs) that have obtained a pediatric indication, particularly in infants and younger children. The study of oxcarbazepine in very young children by Pina-Garza et al.3 in this issue of Neurology is a welcome addition and illustrates many of the advantages as well as the difficulties of doing pediatric drug trials. Why are so few good quality randomized clinical trials of newer AEDs being done in children? Historically, new AEDs were studied primarily in adult males. Recent FDA …

Clinical pharmacokinetics of antiepileptic drugs in children

Clinical pharmacokinetics of antiepileptic drugs in children