In cardiology, B-type natriuretic peptide and the amino terminal segment of its prohormone (NT-proBNP) are important biomarkers. The importance of these peptides as markers for heart disease in pediatric cardiology is reviewed. The peptide levels are dependent on age, assay, and possibly gender. The normal value range and upper limits for infants and children are needed. To determine reference values, data were combined from four studies that measured NT-proBNP levels in normal infants and children using the same electrochemiluminescence assay. The age intervals for the upper limits of normal were chosen for intervals in which no age-dependent change was observed. Statistical analysis was performed on log-transformed data. A total of 690 subjects (47% males) ages birth to 18 years were included in the review. The levels of NT-proBNP were highest in the first days of life, then showed a marked decline in the first week or weeks. The peptide levels continued to decline gradually with age (r = 0.43; p < 0.001). Male and female levels differed only for children ages 10 to 14 years. However, the upper limit of normal did not differ between the boys and girls in any age group. The findings lead to the conclusion that B-type natriuretic peptide (BNP) and NT-proBNP are important markers for heart disease in pediatric cardiology. The levels of NT-proBNP are highest in the first days of life and decrease drastically thereafter. A mild gradual decline occurs with age throughout childhood. Girls have somewhat higher levels of NT-proBNP during puberty.

This review summarizes the present status of physiologically based pharmacokinetic (PBPK) modeling and simulation (M&S) and its application in support of pediatric drug research. We address the reasons that PBPK is suited to the current needs of pediatric drug development and pharmacotherapy in light of the evolution in pediatric PBPK methodologies and approaches, which were originally developed for the purpose of toxicologic evaluation. Also discussed is the current degree of confidence in using PBPK to support pediatric drug development and registration and the key factors essential for robust results and broader adoption of pediatric PBPK M&S.

The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.

ABSTRACT. Objective. To determine plasma levels of N-terminal pro-brain natriuretic peptide (N-BNP) in control children to establish a normal age-dependent range from the neonatal period to adulthood. In addition, plasma concentrations of N-BNP were measured in children with congestive heart failure (CHF) and correlated with ejection fraction and clinical symptoms of heart failure.Methods. For establishing a normal age-dependent range of plasma N-BNP, venous blood samples were taken in 133 control patients from the neonatal period to adulthood (10 days-32 years) and in 31 children with CHF. Plasma N-BNP levels were determined by an enzyme immunoassay. In children (1 month-14 years) with CHF, plasma N-BNP levels were correlated to ejection fraction measured by echocardiography and clinical symptoms of heart failure using the Ross Score.Results. N-BNP levels in control children, adolescents, and adults did not show a significant age-related difference. In control children, the normal range was established between 150 (10th percentile) and 430 fmol/mL (90th percentile). Mean plasma N-BNP in control children was 311 fmol/mL (range: 74 -654 fmol/mL). In 31 children with CHF, the plasma N-BNP levels were significantly higher (mean: 846; range: 219-2718) than in control children. N-BNP levels showed a negative correlation with the ejection fraction (r ‫؍‬ ؊0.53) and a positive correlation with the clinical heart failure score (r ‫؍‬ 0.74).Conclusions. Plasma N-BNP levels reflect the severity of symptoms of heart failure and the impairment of cardiac function in children with CHF. In the future, determination of plasma N-BNP levels may be used as a helpful adjunct to monitor the effect of various treatments for CHF in children. Pediatrics 2002;110(6). URL: http://www.pediatrics.org/cgi/content/full/110/6/e76; N-BNP, children, heart failure, natriuretic peptides.ABBREVIATIONS. BNP, brain natriuretic peptide; N-BNP, Nterminal pro-brain natriuretic peptide; CHF, congestive heart failure; DCM, dilated cardiomyopathy; HLHS, hypoplastic left heart syndrome, FALL, postoperative tetralogy of Fallot; MR, mitral regurgitation; VSD, ventricular septal defect; AVSD, atrioventricular septal defect.T he cardiac natriuretic hormones play an important role in the regulation of extracellular fluid volume and blood pressure. These peptide hormones induce natriuresis, diuresis, and vasodilation and act specifically to counter the effects of the renin-angiotensin-aldosterone system. The natriuretic peptide system allows the heart to participate in the regulation of vascular tone and extracellular volume status. The brain natriuretic peptide (BNP) is a recently discovered natriuretic hormone of cardiac origin. 1 BNP is secreted from the cardiac ventricular myocytes in response to an increase in ventricular wall tension and is related to left ventricular filling pressures. 2 BNP mediates in arterial and venous vasodilation. Human pro-BNP consists of 108 amino acids; processing releases the biologically active 32-amino acid peptide and an ami...

The N-ANP and N-BNP plasma concentrations in healthy neonates showed a marked increase during the first days of age, suggesting that ANP and BNP have physiologic roles in the perinatal circulatory change from fetus to neonate.

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The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

In recent years, the increased interest in pediatric research has enforced the role of physiologically based pharmacokinetic (PBPK) models in pediatric drug development. However, an existing lack of published examples contributes to some uncertainties about the reliability of their predictions of oral drug exposure. Developing and validating pediatric PBPK models for oral drug application shall enrich our knowledge about their limitations and lead to a better use of the generated data. This study was conducted to investigate how whole-body PBPK models describe the oral pharmacokinetics of sotalol over the entire pediatric age. Two leading software tools for whole-body PBPK modeling: Simcyp® (Simcyp Ltd, Sheffield, UK) and PK-SIM® (Bayer Technology Services GmbH, Leverkusen, Germany), were used. Each PBPK model was first validated in adults before scaling to children. Model input parameters were collected from the literature and clinical data for 80 children were used to compare predicted and observed values. The results obtained by both models were comparable and gave an adequate description of sotalol pharmacokinetics in adults and in almost all pediatric age groups. Only in neonates, the mean ratio(Obs/Pred) for any PK parameter exceeded a twofold error range, 2.56 (95% confidence interval (CI), 2.10–3.49) and 2.15 (95% CI, 1.77–2.99) for area under the plasma concentration-time curve from the first to the last concentration point and maximal concentration (Cmax) using SIMCYP® and 2.37 (95% CI, 1.76–3.25) for time to reach Cmax using PK-SIM®. The two PBPK models evaluated in this study reflected properly the age-related pharmacokinetic changes and predicted adequately the oral sotalol exposure in children of different ages, except in neonates.