Developmental Pharmacodynamics Research Articles

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development.

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic-pharmacodynamic (PK-PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK-PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK-PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

Functional Biomarkers: an Approach to Bridge Pharmacokinetics and Pharmacodynamics in Pediatric Clinical Trials.

Over the past 30 years, much has been learned about the impact of development on drug disposition (i.e., pharmacokinetics). This is not true concerning drug action (i.e., pharmacodynamics). As a consequence, in clinical therapeutics and the drug development process, assumptions are often times made that a specific systemic drug exposure that is associated with desired drug action in adults will produce the same response in children. A review of the literature would suggest that this assumption may, in some cases, be an errant one. The relative paucity of information concerning developmental pharmacodynamics is associated with the challenge of assessing and quantitating drug response in vivo in infants and children. An approach to overcome these difficulties has been the evolution of biomarkers that are functional in nature in that they are capable of measuring drug response in both a time and age dependent fashion. The purpose of this review is to illustrate how functional biomarkers capable of assessing drug response/ effect in the developing child are developed and being evaluated for their clinical utility.

How to Improve the Safe and Effective Use of Doxorubicin in Children with Cancer.

Doxorubicin, one of the anthracyclines, is a chemotherapeutic agent widely used to treat several pediatric cancers such as acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, softtissue sarcoma, bone sarcoma, Ewing sarcoma, neuroblastoma, and Wilms tumor. As such, this drug has contributed substantially to the dramatic improvement of the 5-year survival rates for many of these childhood cancers [1]. However, a major potential adverse event of the use of doxorubicin is its cardiotoxicity. More than 50 % of patients will develop asymptomatic cardiac dysfunction, whereas one in six will result in clinical heart failure due to cardiomyopathy [2]. The exact causative mechanism of this devastating adverse event is, despite the fact that doxorubicin has been used for decades in many patients, not fully elucidated. There is more or less consensus about the important role of reactive oxygen species causing cardiac cell damage, progressive myocyte loss that ultimately will result in a decreased cardiac contractility [3]. To date, several clinical risk factors have been linked to the development of doxorubicin-induced cardiotoxicity and these are a higher single as well as total cumulative dose, cardiac irradiation, short infusion time duration, younger age, longer time since the treatment, and female sex [4]. In addition, much more recently, the potentially important role of genetic factors as predictors of doxorubicin-induced cardiotoxicity has been brought to our attention [5]. Multiple genetic variants in several genes associated with this cardiotoxicity have been identified [6]. However, until now, the currently available knowledge about both the clinical as well as the genetic risk factors has never resulted in sufficient discriminatory power to divide patients into groups with a high or low risk of developing cardiotoxicity. In this issue of the journal, Voller and colleagues have described a population pharmacokinetic model of doxorubicin in children in which they have used a power function to describe the relation between doxorubicin clearance and age [7]. They were able to show, for the first time, that the pharmacokinetics (PK) of doxorubicin in infants and children with cancer are age dependent. Clearly, this finding might eventually assist in designing a more tailored, safe, and effective dosing regimen for the use of doxorubicin in children with cancer. However, before this demonstrated lower clearance of doxorubicin in infants and children younger than 3 years of age will be able to change the currently used dosing regimens in pediatric patients with cancer, there is an absolute need to not only consider developmental PK but also, and probably more importantly, developmental pharmacodynamics (PD). At first glance, based on the demonstrated lower total body clearance, it seems that we need less doxorubicin in this group of young patients to reach the same amount of doxorubicin exposure as compared with older children and adolescents. However, what do we really know about the dose-concentration-effect relationship in children with cancer between 1 and 18 years of age? In other words, there is an urgent need to better This commentary refers to the article available at doi:10.1007/s40262-015-0272-4.

Changing the Outcomes of Pediatric Drug Trials: APNs Making a Difference

Children are unique, growing, and developing individuals with potentially differing rates of drug absorption and metabolism, and one cannot assume that they will respond to drugs in a similar manner as adults. These differences in developmental pharmacodynamics may increase the risks or enhance the benefits of drugs when they are administered to pediatric patients, and the distinctions change as children move from the neonatal period through childhood and then puberty. Despite these variations, the safety and efficacy of many drugs used in children have not been studied or approved by the Food and Drug Administration (FDA; Bourgeois et al., 2012; National Heart Lung and Blood Institute [NHLBI], 2012).

Understanding Developmental Pharmacodynamics

Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some antidepressants in children. GABA(A) receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the mu opioid receptor. An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual 'bottom up' (ontogeny knowledge driven) and 'top down' (pediatric pharmacokinetic-pharmacodynamic studies) approach.

Developmental pharmacodynamics of cyclosporine.

To determine the relationship between human development and in vitro cyclosporine (INN, ciclosporin) pharmacodynamics. Fifty-six subjects ranging in age from 3 months to 39 years were studied in this prospective laboratory investigation at a university children's hospital and clinical pharmacology laboratory. Peripheral blood monocytes were separated from whole blood and cultured with phytohemagglutinin A (5 microg/mL) and cyclosporine (0, 6.25, 12.5, 25, 50, 100, 500, 1000, 2500, and 5000 ng/mL). Peripheral blood monocytes cultures were assayed for cell proliferation and supernatant interleukin-2 concentration with use of radionuclide DNA tagging and enzyme-linked immosorbent assay, respectively. After concentration-effect modeling, summary pharmacodynamic parameters, including the maximal drug effect (Emax) and cyclosporine concentration at which 50% of maximal effect (IC50) and 90% of maximal effect (IC90), were determined. These parameters were compared between four consecutive subject age groups: infants (0-1 years), children (>1-4 years), preadolescents (>4-12 years), and adults (>12 years). The peripheral blood monocytes of the infants showed a twofold lower mean IC50 (peripheral blood monocyte proliferation) and sevenfold lower mean IC90 (interleukin-2 expression) than peripheral blood monocytes from older subjects. The three older age groups were similar with respect to mean IC50 and Emax (peripheral blood monocyte proliferation). Lymphocyte subtype proportions measured in peripheral blood monocytes preparations from each age group were generally similar. The experimental conditions (eg, general anesthesia and cyclosporine solvents) did not affect peripheral blood monocytes proliferation, but the highest experimental cyclosporine concentration (ie, 5000 ng/mL) was associated with decreased peripheral blood monocytes viability. Cyclosporine pharmacodynamics in vitro are related to age. This factor, if neglected, may be a source of iatrogenic risk during pediatric immunosuppressive therapy.

Psychopharmacology across life span: focus on developmental pharmacodynamics

Psychopharmacology across life span: focus on developmental pharmacodynamics

Psychopharmacology across life span: focus on developmental pharmacodynamics

Psychopharmacology across life span: focus on developmental pharmacodynamics