Current Pharmaceutical Design - Volume 23, Issue 38, 2017

Background: Effective and safe pharmacotherapy in an individual neonate necessitates understanding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a specific drug together with the characteristics of this neonate. Methods: Developmental PK hereby provides estimates of the concentration-time profile. Multiple maturational, disease and treatment related differences can result in differences in PK and probably also in PD in neonates compared to other populations. All these PK processes (absorption, distribution, metabolism and elimination, ADME) display maturation but are also affected by non-maturational covariates. Maturational covariates relate to age or weight dependent changes, while non-maturational covariates relate to variables in disease, environment, treatment – including co-medications - or genetic background. Results: We will describe general PK related aspects of ADME in neonates with emphasis on both maturational and non-maturational covariates of the variability observed, followed by compound specific illustrations (tramadol, amikacin) to further underscore the impact and interaction of these maturational and non-maturational changes. Conclusion: Future efforts should focus on integration of the already available knowledge and the collection of data on the impact of non-maturational covariates. These kinds of PK efforts will become clinically important when subsequently linked to PD, ultimately covering both wanted effects and undesired side-effects.

Background: The development of appropriate pharmaceutical formulations for routine neonatal practice is challenging because of the developmental characteristics and the need for it to be specifically ageappropriate. This has led to wide use of extemporaneous formulations, which lack standardized procedures that can result in medication errors in clinical practice resulting in suboptimal efficacy and safety concerns. Methods: We have reviewed the most recent literature on formulations and pharmaceutical excipients. Results: We present the issues related with the lack of age-appropriate formulations, discuss the importance and extent of exposure to pharmaceutical excipients known to be harmful to neonates, indicate ways that can reduce exposure to excipients of concern, and review challenges of the design of age-appropriate drug formulations and dosage forms/drug delivery systems for neonates. Finally, we summarize novel approaches regarding drug delivery for neonates. Conclusion: Novel approaches in age-appropriate drug delivery should overcome the present obstacles and improve the quality of medicines, thus avoiding errors in treatment and improving the management of neonates. Further basic researches on discovering new technologies and modern formulations, using in vitro testing systems as well as preclinical and clinical trials, are needed to improve the feasibility, practicality and safety of new formulations, including research on pharmaceutical excipients.

Introduction: Therapeutic drug monitoring (TDM) refers to the interpretation of quantified drug concentrations in strategically timed samples of bodily fluids, with the aim to maximize therapeutic benefit, while minimizing toxicity. In essence, TDM criteria for neonates are similar to those for adults, but specific issues should be considered. This review focusses on the relevance of these specific issues: larger variability in pharmacokinetics (PK), and non-PK related factors, sampling opportunities, analytical techniques, therapeutic range. Specific issues: Larger variability in PK, and non-PK related factors in neonates compared to adults result in a less clear relation between the administered dose and the concentration measured. Sophisticated dosing regimens derived from population PK-models can partly overcome this variability, thereby reducing the need for TDM. Dosing can be further individualized using Bayesian forecasting as a tool for TDM. Besides PK related factors, concentrations of endogenous substances (e.g. immunoglobulin A, plasma protein) in neonates differ from those in adults, which may complicate interpretation of measured drug concentrations. Blood sampling opportunities in neonates are limited by the small blood volume and the need to minimize painful procedures. Dried blood spot sampling may be less invasive. This method has been facilitated by more sensitive analytical techniques, such as chromatography followed by mass spectrometry. For the same reason, saliva is gaining attention as an alternative non-invasive bodily fluid. Lastly, reference values for therapeutic ranges of drugs in neonates are mostly adapted from adult studies, although pharmacodynamics may be quite different in neonates. This review concludes with recommendations for future research on these specific issues.

Background: Historically, neonatal therapeutic interventions were derived from adult therapeutics, and tragedies resulting from this approach have demonstrated differences in the pathophysiologic and developmental processes between neonates and older patients. Over the past 3 decades, researchers and collaborative research networks have made progress in the systematic evaluation of neonatal therapies, yet most neonatal therapeutic products have been incompletely assessed for safety and efficacy, and remain unlabeled and unapproved. Approach: This work describes the legislative initiatives that have stimulated an increase in pediatric and neonatal studies. It highlights examples of successful neonatal drug studies that have resulted in informative neonatal labeling changes, as well as studies that have produced incomplete information. Strategies that support the design of successful studies, including targeting specific subpopulations, modeling and simulation to inform dose selection, innovative design strategies, biomarkers, and endpoints are discussed. Multi-stakeholder consortia such as the International Neonatal Consortium (INC), are working to improve the tools needed for the development of neonatal therapies. These research tools may be used by trial networks to inform consistent and efficient multicenter studies. Conclusion: More data are needed to support safe and effective use of drugs in neonates, and to obtain these data, a thorough understanding of pathophysiology, drug disposition, biomarkers, and clinically-meaningful endpoints is required. This information will be derived from clinical trials, registries, real-world evidence, and the medical literature. Collaboration of consortia and the development of research networks are essential to achieving these goals.

Background: β-lactams are among the most frequently prescribed antibiotics for the treatment of neonatal sepsis. Survival of extremely preterm neonates necessitates an improved understanding of how β-lactams should be used in this vulnerable population. Appropriate dosing regimens for neonates remain unclear. We reviewed available data on the pharmacokinetics (PK) of β -lactam drugs in neonates. Pharmacokinetic/ pharmacodynamic (PK/PD) efficacy index surrogates and minimum inhibitory concentrations (MICs) used to support dosing regimens recommendation in the studies were also investigated. Methods: A comprehensive literature search was undertaken to identify studies that have investigated the PK/PD of β-lactam drugs in neonates. Results: Data available for the PK/PD of β-lactams in neonates are limited but confirm the importance of weight, gestational age and postnatal age as markers of growth and renal maturation. The contribution of tubular secretion in addition to glomerular filtration is highlighted. The development of methods to assay β-lactam protein binding in vivo has added greater understanding. Modelling and simulation techniques have aided dosing optimisation. However, there remains a gap in the understanding of PD parameters and the appropriate PK/PD index to target for improved clinical outcome which partly explains the various dosing recommendations. Improved data on the efficacy of β -lactams are needed in a context of increasing global antimicrobial resistance and variable geographic MIC distribution. Conclusion: Prospective in vivo studies are required to validate PK/PD indexes associated with clinical efficacy. Current antimicrobial stewardship efforts should integrate PK/PD principles and dosing optimization, taking into account susceptibility of isolated microorganisms.

Background: Intravenous paracetamol (acetaminophen) has not been licensed for analgesia in preterm neonates or infants < 2 years, respectively, in Europe and the United States. A variety of dosing regimens is therefore used off-label. Because evidence supports the use of the same target mean steady state paracetamol concentration (Cssmean, 9-11 mg/L) for pain relief in neonates compared to older children and adults, dosing regimens based on this Cssmean were evaluated in a two-step approach. Methods: First, a systematic search was performed to provide pharmacokinetic (PK)-based dosing guidelines for pain in neonates (with subsequent searches on safety in these papers). Second, concentration-time profiles based on these dosing guidelines were generated to provide a dosing advice for paracetamol to treat neonatal pain. Results: Of 2334 potentially relevant articles, 9 studies were included. For typical term neonates, dosages specified in packaging (labels) resulted in Cssmean below target (7.65 mg/L), while dosages from investigator-initiated studies resulted in either a Cssmean above (15.31), or around the target (11.78 and 10.21) for (pre)term neonates >32 weeks. Only one study suggested a dosing resulting in a tailored concentration (8.7) in preterm neonates <32 weeks. Conclusion: A loading dose 20 mg/kg, followed by 10 mg/kg/6h is recommended for 32-44 weeks' neonates, which is supported by short-term safety. For neonates < 32 weeks, a loading dose of 12 mg/kg and a maintenance dose of 6mg/kg/6h seems to lead to the target Cssmean, though additional clinical studies are needed to support its safety.

Background: Circulatory failure in preterm and term newborn infants is commonly treated with inotropes or vasoactive medications. In this structured literature review, the available data on pharmacodynamic effects of the inotropes adrenaline, dobutamine, dopamine, levosimendan, milrinone, noradrenaline, and the vasoactive drugs vasopressin and hydrocortisone are presented. Methods: Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria which were human clinical trials published after 2000. Results: Out of 101 identified eligible studies only 22 studies met the criteria for evidence based practice guidelines level I to IV. The most prevalent pharmacodynamic effects were increase in blood pressure and/or heart rate, which were also the most frequently studied circulatory parameters. Conclusion: This review demonstrates the need for further systematic studies on all reviewed drugs with incorporation of novel non-invasive biomarkers in this vulnerable patient group, for more timely and appropriate treatment for clinical efficacy.

Background: although neonatal pain management has seen huge improvements in the past years, many gaps between knowledge and practice still exist. Objective: to give the reader the state of the art of actual pain management and treatment. Methods: a literature review was done on the physiopathology of pain, sex differences in the perception of pain, epidemiology, non-pharmacological treatment and developmental care approach, pharmacological treatment with pharmacokinetics and pharmacodynamics approaches. Conclusion: despite an increasing knowledge in the field of neonatal pain, many gaps and questions remain, especially relative to the lack of assessment, prevention and treatment of painful procedures, appropriate drugs and dosing to support the well-being and the brain development of this highly vulnerable population.

Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also – and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies.

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.

Introduction: In the Neonatal Intensive Care Unit (NICU), prematurely born infants undergo a range of skin breaking and painful procedures. At the same time, the spinal nociceptive system is in a sensitive developmental stage. Both neonatal repetitive painful procedures and their treatment can induce plasticity of the neonatal spinal nociceptive system, causing long-lasting alterations to pain processing and pain reactivity. Methods: This review focuses on developmental processes related to the nociceptive network in the spinal dorsal horn and more specifically at mechanisms related to 1. Modulation of afferent systems; 2. The role of interneurons; 3. Descending inhibitory pathways; and 4. The central neuro-immune responses and microglial cell responses. The effects and possible mechanisms underlying the long-term effects of repetitive painful procedures on the developing nociceptive system as well as subsequent pharmacological treatment (acetaminophen, morphine) in early life are discussed. Results: Repetitive stimulation of the nociceptive system in a rat model with use of needle pricks in the hind-paw closely mimics the clinical situation for infants in the NICU. Conclusion: Activity dependent plasticity in early postnatal life induces long-lasting alterations that then may cause altered pain perception in adulthood. For a future choice of optimal analgesic drugs these considerations have to be taken into account beyond the classical classes of drugs used nowadays.

Background: Finding the right drug-dosage for neonates is still a challenge. Until now, neonatal doses are extrapolated from adults and children doses. However, there are differences between neonatal and adult kidney physiology that should be considered, especially when it comes to drug metabolism and/or transport. Studying renal drug disposition in neonates is limited by the lack of reliable human cell models. Objective: To illustrate the feasibility of developing an in vitro model for neonatal proximal tubule epithelial cells (nPTECs) to study renal drug disposition at this age. Method: nPTECs were isolated from urine samples of neonates of different gestational ages and were conditionally immortalized using a temperature sensitive SV40T antigen and human telomerase hTERT. Cell clones were characterized on gene expression level for PTEC markers such as P-glycoprotein (ABCB1), aquaporin1 (AQP1), and organic cation transport protein 2 (SLC22A2), and for kidney progenitor cell and podocyte markers. In addition, protein expression and functional assessment were performed for P-gp and OCT2. Results: We established 101 clonal cell lines of conditionally immortalized nPTECs derived from neonatal urines. Characterization of primary cells lines showed expression of genes from different cell types such as progenitors, PTECs and podocytes, however the developed conditionally immortalized nPTECs only expressed proximal tubule markers. Quantitative PCR analysis confirmed the expression of proximal tubule markers in nPTECs similar to the adult control PTECs. P-gp was expressed in nPTECs derived from the different gestational ages with a similar functionality compared with adult derived PTECs. In contrast, OCT2 functionality was significantly lower in nPTEC cell lines compared with adult PTECs. Conclusion: We demonstrate the feasibility of culturing proximal tubule epithelial cells with high efficiency from urine of neonates. These cells expressed PTEC-specific genes and functional drug transporters. The cell model presented is a valuable tool to study proximal tubule physiology and pharmacology in newborns. In addition, we demonstrate the physiological differences between the neonatal and adult kidney, which emphasizes the importance of studying drug disposition in neonatal models instead of extrapolating from adult data.

Background: Drug effect evaluation is often based on subjective interpretation of a selection of patient data. Continuous analyses of high frequency patient monitor data are a valuable source to measuring drug effects. However, these have not yet been fully explored in clinical care. We aim to evaluate the usefulness and applicability of high frequency physiological data for analyses of pharmacotherapy. Methods: As a proof of principle, the effects of doxapram, a respiratory stimulant, on the oxygenation in preterm infants were studied. Second-to-second physiological data were collected from 12 hours before until 36 hours after start of doxapram loading dose plus continuous maintenance dose in seven preterm infants. Besides physiological data, plasma concentrations of doxapram and keto-doxapram were measured. Results: Arterial oxygen saturation (SpO2) increased after the start of doxapram treatment alongside an increase in heart rate. The respiratory rate remained unaffected. The number of saturation dips and the time below a saturation of 80%, as well as the area under the 80%-saturation-time curve (AUC), were significantly lowered after the start of doxapram. The AUC under 90% saturation also significantly improved after start of doxapram. Plasma concentrations of doxapram and keto-doxapram were measured. Conclusion: Using high-frequency monitoring data, we showed the detailed effects over time of pharmacotherapy. We could objectively determine the respiratory condition and the effects of doxapram treatment in preterm infants. This type of analysis might help to develop individualized drug treatments with tailored dose adjustments based on a closed-loop algorithm.

Background: Local delivery of drugs to the lungs of newborn infant represents an unmet need as no drugs have been approved. Potential benefits could be large. Development of aerosol for delivery of drugs to infants and newborn offers huge potential for better therapy. Newborn infants present unique challenges with regard to aerosol therapy. Efficient deposition of aerosolized medications on the neonate airway surface is hampered by anatomical features such as small airway geometries and physiological features such as exquisitely small tidal volumes, rapid breathing and unfavorable inhalation:exhalation ratios. Methods: The selection of aerosol generators capable of delivering any more than a few percent of the nominal drug dose to the airways remains extremely limited with nebulizers and pressurized metered dose inhalers being predominantly used. Further hampering the development of bespoke high performance aerosol therapy for neonates is the as yet unknown ideal droplet size. Results: Droplet size is a critical determinant of the amount of aerosol that escapes the patient circuit, becoming available to the patient, and subsequently the location of deposition within the lung. It is assumed that smaller is better at traversing the tortuous path from aerosol generator to airway surface. To date, patient interface has been shown to have little effect with respect to delivered dose, but some may provide advantage with respect to ease of use and patient acceptance. Conclusion: The present review iteratively describes the difficulties in achieving optimized aerosol drug delivery in neonates. We suggest possible technical solutions aimed at improving delivery and developing a platform for increased reliability and reproducibility of dosing such that new and existing medications may exploit the potential advantages of aerosol therapy in the neonate population.

Background: Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal mortality and neurological morbidity, even despite hypothermia treatment. Neuronal damage in these infants is partly caused by the production of superoxides via the xanthine-oxidase pathway and concomitant free radical formation. Allopurinol is a xanthine-oxidase inhibitor and can potentially reduce the formation of these superoxides that lead to brain damage in HIE. Methods: The aim of this review is to provide an overview of the animal and clinical data about the neuroprotective effect of allopurinol in HIE and the relevant mechanisms leading to brain injury in HIE. Results: A possible neuroprotective effect of allopurinol has been suggested based on several preclinical studies in rats, piglets and sheep. Allopurinol seemed to inhibit the formation of superoxide and to scavenge free radicals directly, but the effect on brain damage was inconclusive in these preclinical trials. The neuroprotective effect was also investigated in neonates with HIE. In three small studies, in which, allopurinol was administered postnatally and a pilot and one multi-center study, in which, allopurinol was administered antenatally, a possible beneficial effect was found. After combining the data of 2 postnatal allopurinol studies, long-term follow-up was only beneficial in infants with moderate HIE, therefore, large-scale studies are needed. Additionally, safety, pharmacokinetics and the neuroprotective effect of allopurinol in other neonatal populations are discussed in this review. Conclusion: The available literature is not conclusive whether allopurinol is a neuroprotective add-on therapy in infants with HIE. More research is needed to establish the neuroprotective effect of allopurinol especially in combination with hypothermia.

Introduction: The neonatal population remains one of the populations in which appropriate dosing regimens are still lacking, resulting in a large off-label or unlicensed use. Clinical research in these small infants remains a challenge, which sparks the need for modeling and simulation as an additional tool for neonatal drug research. Methods: The use of physiologically based pharmacokinetic modeling in preterm and term neonates is investigated. Results: Throughout the last decade, the use of this modeling technique in this vulnerable population has received increased attention, but still many knowledge gaps exist. Firstly, an overview of the top-down, bottom-up and middle-out approach is given, and then these different modeling tools regarding feasibility and appropriate use are compared. The challenges in applying PBPK to this young population are highlighted and possible solutions are presented. Examples of applications were found in literature and a preference for the combination of a pure bottom- up approach with clinical data (the “middle-out” approach) was detected. Conclusion: Perspectives to further apply this powerful modeling methodology in this population are described in order to become ‘the tool’ for the design of First-in-Human and First-in-Neonate trials, and the individualization of dosing in these therapeutic orphans.

Background: Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates. Methods: We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates. Results: The use of blood pressure measurements, heart rate variability, functional echocardiography, nearinfrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the ‘brain circulation model’, the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools. Conclusion: The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. Furthermore, besides short-term drug effects, long-term outcome of drug therapy in neonates also warrants further attention.

Background: Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants. Methods: In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 μg/kg), that increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter, a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational ages were included. Results: IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 μg/kg/24 h and the infusion was prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days. Conclusion: The purpose has been to ensure high-quality research into the development of a new drug for preterm infants. We hope that our work will help to establish a new standard for the testing of medications for preterm infants.