Pediatric pharmacology: current efforts and future goals to improve clinical practice

Abstract

Interest in pediatric pharmacology has increased over the past two decades. With few exceptions, research efforts are currently, however, still limited to pharmacokinetic (PK) queries on single drugs in a limited number of subjects. It is now time to move forward and integrate and generalize the PK information that is currently available more efficiently across different drugs and different populations. Additionally, for pediatric patients to truly benefit from pharmacological research efforts, the knowledge that is obtained in these studies needs to be translated into dosing recommendations that are subsequently prospectively evaluated in adequately powered randomized clinical trials. Finally, as drug effects and safety are the result of both PK and pharmacodynamic (PD) processes and as developmental changes may occur in both processes, it is essential for PK studies to be followed-up by PD studies when dose-adjustments based on PKs alone have been proven insufficient. In this report, examples illustrating this approach are provided. As PD studies in children are generally more complicated to perform than PK studies, this is where a big challenge in pediatric pharmacological research still lies.

Keywords:

• clinical pharmacology
• dosing recommendations
• models
• pediatrics

1. Introduction

Toward the end of last century, society grew more aware of the need for pharmacological research in children. Although asking and obtaining consent from parents may still be challenging, previously conceived ethical conflicts about performing ‘experiments’ in children have been set aside, because even though pediatricians around the world had gained a significant body of knowledge on how to dose commonly used drugs, it was realized that without evidence-based dosing recommendations, any pharmacological treatment of a child could be considered an experiment. In addition, the development of computational-intensive data analysis techniques has allowed for the analysis of data obtained under restrictive circumstances arising from practical and ethical limitations in the pediatric population, as well as for the integration of data from various sources [1,2]. Moreover, legislation on pediatric study requirements in filings for market approval of new drugs and governmental research funding programs (e.g., Pediatric Rule [FDA, 1998], Best Pharmaceuticals for Children Act [FDA, 2002], Paediatric Regulation [EMEA, 2007] and 7th Research Framework Programme [EU, 2007 – 2013]) have further stimulated pharmacological research in this vulnerable population.

2. Current efforts

Pharmacological drug responses should not be directly linked to drug dose. As drug responses result from pharmacokinetic (PK) processes, linking drug doses to drug exposure, and pharmacodynamics (PD) processes, linking drug exposure to drug response, both types of processes need to be considered when optimizing dosing recommendations. When disease progression and the exposure–response relationship of a drug can be assumed to be equal in children and adults, studying age-related differences in PK only will suffice [3]. Moreover, identifying and quantifying PD processes underlying drug response require detailed knowledge of PK processes. Hitherto, most pediatric pharmacological research has therefore set out to study drug PK.

Even today, despite the availability of advanced data-analysis techniques [1,2], a considerable number of pediatric PK studies focus on descriptive, secondary PK parameters like area under the observed concentration–time curve, and peak and trough concentrations. Major drawbacks of methods based on descriptive parameters are that results are dependent on and limited to a particular study design and that they do not provide insight in the processes underlying the drug PK or in the developmental changes in these processes in the pediatric population. By quantifying primary PK parameters or physiological PK parameters using state-of-the-art modeling approaches [1,2], study results may provide more (patho)physiological insight.

When population pharmacokinetic (PopPK) analyses are used, primary PK parameters like clearance, distribution volume and absorption rate constants are derived from concentration–time data. Since data from all individuals are analyzed simultaneously, it allows for the analysis of sparse and unbalanced data obtained during routine clinical practice, thereby reducing the experimental burden on individual patients, while still obtaining accurate and precise PK parameters [1]. Covariate relationships in these models describe how patient or treatment characteristics are related to inter-individual variability in drug PK or PD parameters. These relationships can range from simple linear forms, to highly advanced bodyweight-dependent exponent relationships [4]. Provided that a model is adequately validated [5], primary PK parameters and covariate relationships from these models are applicable to all patients within a studied population, allowing for predictions to be made about drug exposure resulting from different treatment designs in that population. Moreover, the covariate relationships obtained in these analyses can be directly used as the basis for dosing recommendations [6,7].

Physiologically based PK (PBPK) modeling integrates system-specific information on physiological parameters and anatomical measurements and how these change with the development of children and disease progression, with in vitro information on how drugs with specific physicochemical properties interact with the (patho)physiological system [2,8]. These models require a vast amount of information, and currently experimental data on some physiological and anatomical measurements and on the variability in these measurements in different pediatric (sub)populations are limited. However, this information needs to be obtained only once for this approach to be generalizable to drugs with a wide range of physicochemical properties and to patients with a wide range of conditions. Currently, PBPK modeling has already been proven useful in predicting pediatric drug clearances from adult data [9], however, detailed dosing recommendations cannot be directly derived from these models and need to be obtained after extensive simulations [10].

3. Future goals

Dedicated PK studies for each drug in each pediatric subpopulation are not feasible, due to the large amount of resources that this would require and the limited number of pediatric patients available for inclusion in studies. A shift in focus is therefore needed, developing new methodologies that integrate PK information efficiently. PopPK models are, for instance, based on outcome measures and yield covariate relationships that can be used directly for dosing recommendations, but these models are only applicable to specific drugs in specific populations. PBPK models on the other hand are much more generalizable, but require information that may be difficult to obtain experimentally in children [8]. Our group is currently investigating how to combine these two approaches, making PopPK results more generalizable by extrapolating covariate relationships on clearance between drugs that share a common elimination pathway, thereby differentiating between drug-specific properties and generalizable system-specific properties of PopPK models [11-14]. Alternatively, PopPK techniques could be combined with PBPK modeling to derive PBPK parameters from outcome measures instead of measuring them experimentally.

In addition to integrating PBPK and PopPK strategies, it is important that research efforts do not stop after reporting PK models for a certain drug. Pediatric patients can only benefit from insights in developmental changes in PK processes, if results from PK studies are translated into dosing recommendations [6]. Covariate relationships from PopPK models and model-based simulations can, for instance, be used to develop dosing recommendations that lead to exposure measures that hit a certain target or that stay within a predefined window, as illustrated for aminoglycosides in neonates [15].

Unfortunately, age-appropriate target exposures in the pediatric population may not be known for some drugs. Therefore, it is imperative that future pediatric pharmacological research is directed toward following-up PK studies with PD studies when prospective clinical studies on PK-derived dosing recommendations suggest a need for this, so that age-appropriate target exposures are obtained that can be used in model-based simulations for dose optimization. As illustrated in Figure 1, it was found that model-derived morphine dosing in neonates and young infants that corrects for age-related difference in PK, improves patient care by reducing overexposure in the very young and reducing the risk of treatment failure in older patient, but still yields differences in the requirements of rescue doses [7]. For this particular drug, further PD research identifying developmental differences in (patho)physiology is therefore imperative. Only once-dosing recommendations that take both drug PK and PD into account have been prospectively evaluated, do we have pediatric dosing recommendations with a level of evidence that we would consider to be acceptable in adults [6].

Figure 1. Morphine infusion rates for postoperative analgesia for neonates with postnatal age (PNA) younger than 10 days (left) and older infants up to 1 year (right). Initial rates according to a model-derived dosing algorithm (2.5 µg/kg^1.5/h when PNA < 10 days and 5 µg/kg^1.5/h when PNA > 10 days) represented by solid lines, average actual infusion rates for individual patients taking dose adjustments based on individual needs into account indicated with symbols, and infusion rates according to the traditional dosing regimen in our facilities (10 µg/kg/h) indicated by dashed line.

PD research in children does however come with its own set of challenges. End points based on self-report cannot be used in patients in the first few years of life, making this research highly dependent on the availability of biomarkers [16]. For diseases for which validated biomarkers are not available in adults or for diseases that present differently in children compared with adults, functional biomarkers for the pediatric population are especially difficult to obtain and development of such biomarkers should be prioritized. First steps in this area have been taken [17,18], but more research in this area is desperately needed.

4. Expert opinion

Pharmacological research in children is still needed to improve safe and effective drug treatment in this population. Although research efforts have increased over the past two decades, they are to a large degree limited to the PK of single drugs in a limited number of patients and still sometimes rely on descriptive PK parameters. It is time to realize that drug PK or even drug exposure is not the ultimate goal of pharmacotherapy and therefore obtaining PK parameters should not be the primary goal of pediatric pharmacological queries anymore.

Time has come to take the next steps forward in pediatric pharmacological research. Instead of developing yet another PopPK model for a drug that has been extensively studied already, we need to focus on developing methods that allow us to integrate and generalize PK information that is already available. These methods should combine PopPK and PBPK approaches, differentiate between drug-specific and system-specific properties of pharmacotherapy and combine system-specific information from various sources such that this can easily be used to derive pediatric dosing recommendations for many drugs with limited resources [11-14]. Moreover, to actually improve patient care we need to translate our current academic knowledge of developmental changes in drug PK to improved dosing recommendations for pediatric patients [6,15], with subsequent proof-of-principle studies such as adequately powered randomized controlled trials as an essential step forward [6,7]. Finally, when differences in PK alone are found to not be the sole source of difference in drug response between pediatric patients, research needs to be focused on studying age-related changes in PD processes, which is where the biggest challenge in pediatric pharmacological research currently lies. Since the combination of PK and PD processes is ultimately responsible for pharmacological effects, detailed understanding of both processes is needed to let children optimally benefit from pharmacological treatment.

Declaration of interest

CAJ Knibbe received support from the Innovational Research Incentives Scheme (Vidi grant, July 2013) of the Dutch Organisation for Scientific Research (NWO). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes