Challenges in conducting paediatric trials with off-patent drugs.

INTRODUCTION: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge. AIM: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement. DISCUSSION: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug. CONCLUSION: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life.

Therapeutic Drug Monitoring in Neonates: What Makes them Unique?

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.

Sildenafil and retinopathy of prematurity risk in very low birth weight infants.

OBJECTIVE: To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants. STUDY DESIGN: We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003 to 2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil before first eye exam to three nonexposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression. RESULT: Of the 57 815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 nonexposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs nonexposed groups (17/81 (21%) vs 38/243 (16%), P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed vs nonexposed infants (odds ratio=1.46, 95% confidence interval=0.76 to 2.82, P=0.26). CONCLUSION: We did not observe an association between risk of severe ROP and sildenafil exposure before first eye exam in this cohort of premature infants.

Possible effects of repeated exposure to ibuprofen and acetaminophen on the intestinal immune response in young infants.

There has been an exponential increase in the frequency of immune deviations in young children. Consequently, research investigating environmental causes for this increase has become a Public Health priority. We have summarized the experimental observations and epidemiological data that could link repeated acetaminophen and ibuprofen exposure in early infancy to this increase. Recent observations on the maturational immunity of the intestinal sub-mucosal lamina propria underscore indeed the importance of prostaglandins (PGE2s). PGE2 appearing at this sub-mucosal level is a product of arachidonic acid metabolism mediated by type-2 cyclooxygenase (COX-2) situated on the membrane of many immune cells. Moreover, it seems that acetaminophen - like ibuprofen - also carries a non-selective inhibitory action on peripheral COXs, besides its central action. This inhibitory action of acetaminophen on COX2 only relates to physiological, low arachidonic acid concentrations. This explains the difference in anti-inflammatory effects. The impact of repeated inhibition of mucosal PGE2 synthesis due to COX-inhibitor exposure on maturational immunity has been demonstrated in animal experiments. Repeatedly exposed young animals do not develop tolerance to food antigens and exhibit autoimmune deviations. Several recent epidemiological studies have also reported on the magnitude of acetaminophen and ibuprofen exposure in children and the increase in immune deviations, it is important to better understand the potential negative impact of repeated inhibitions of prostaglandin synthesis by COX2s during infancy. Since acetaminophen and ibuprofen are commonly administered analgesics and antipyretics, a well-designed prospective strategy for pharmacovigilance and -epidemiology of COX-inhibitor exposure in infancy is urgently needed.

Neonatal drug therapy: The first frontier of therapeutics for children.

Knowledge about the safe and effective use of medicines in neonates has increased substantially but has resulted in few label changes. Drugs developed for use in adults are reshaped and tailored to specific neonatal indications. However, the use of drugs in neonates should not only mirror adult pharmacotherapy, but should be driven by their own specific needs. Therefore, building collaborative networks may assist to develop a newborn-driven research agenda addressing their clinical needs and diseases.

Intestinal fatty-acid binding protein and metronidazole response in premature infants.

OBJECTIVES: In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection. STUDY DESIGN: We conducted an intravenous metronidazole pharmacokinetic study, collecting ≤3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates. RESULTS: Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I-FABP concentration (p = 0.006). CONCLUSION: While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants.

Emerging biomarkers and metabolomics for assessing toxic nephropathy and acute kidney injury (AKI) in neonatology.

Identification of novel drug-induced toxic nephropathy and acute kidney injury (AKI) biomarkers has been designated as a top priority by the American Society of Nephrology. Increasing knowledge in the science of biology and medicine is leading to the discovery of still more new biomarkers and of their roles in molecular pathways triggered by physiological and pathological conditions. Concomitantly, the development of the so-called "omics" allows the progressive clinical utilization of a multitude of information, from those related to the human genome (genomics) and proteome (proteomics), including the emerging epigenomics, to those related to metabolites (metabolomics). In preterm newborns, one of the most important factors causing the pathogenesis and the progression of AKI is the interaction between the individual genetic code, the environment, the gestational age, and the disease. By analyzing a small urine sample, metabolomics allows to identify instantly any change in phenotype, including changes due to genetic modifications. The role of liquid chromatography-mass spectrometry (LC-MS), proton nuclear magnetic resonance (1H NMR), and other emerging technologies is strategic, contributing basically to the sudden development of new biochemical and molecular tests. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are closely correlated with the severity of kidney injury, representing noninvasive sensitive surrogate biomarkers for diagnosing, monitoring, and quantifying kidney damage. To become routine tests, uNGAL and KIM-1 should be carefully tested in multicenter clinical trials and should be measured in biological fluids by robust, standardized analytical methods.

Metabolomics in neonatology: fact or fiction?

The newest 'omics' science is metabolomics, the latest offspring of genomics, considered the most innovative of the 'omics' sciences. Metabolomics, also called the 'new clinical biochemistry', is an approach based on the systematic study of the complete set of metabolites in a biological sample. The metabolome is considered the most predictive phenotype and is capable of considering epigenetic differences. It is so close to the phenotype that it can be considered the phenotype itself. In the last three years about 5000 papers have been listed in PubMed on this topic, but few data are available in the newborn. The aim of this review, after a description of background and technical procedures, is to analyse the clinical applications of metabolomics in neonatology, covering the following points: gestational age, postnatal age, type of delivery, zygosity, perinatal asphyxia, intrauterine growth restriction, prenatal inflammation and brain injury, respiratory, cardiovascular renal, metabolic diseases; sepsis, necrotizing enterocolitis and antibiotic treatment; nutritional studies on maternal milk and formula, pharma-metabolomics, long-term diseases. Pros and cons of metabolomics are also discussed. All this comes about with the non-invasive collection of a few drops of urine (exceptionally important for the neonate, especially those of low birth weight). Only time and large-scale studies to validate initial results will place metabolomics within neonatology. In any case, it is important for perinatologists to learn and understand this new technology to offer their patients the utmost in diagnostic and therapeutic opportunities.

Optimising the management of fever and pain in children.

Fever and pain in children, especially associated with infections, such as otitis media, are very common. In paediatric populations, ibuprofen and paracetamol (acetaminophen) are both commonly used over-the-counter medicines for the management of fever or mild-to-moderate pain associated with sore throat, otitis media, toothache, earache and headache. Widespread use of ibuprofen and paracetamol has shown that they are both effective and generally well tolerated in the reduction in paediatric fever and pain. However, ibuprofen has the advantage of less frequent dosing (every 6-8 h vs. every 4 h for paracetamol) and its longer duration of action makes it a suitable alternative to paracetamol. In comparative trials, ibuprofen has been shown to be at least as effective as paracetamol as an analgesic and more effective as an antipyretic. The safety profile of ibuprofen is comparable to that of paracetamol if both drugs are used appropriately with the correct dosing regimens. However, in the overdose situation, the toxicity of paracetamol is not only reached much earlier, but is also more severe and more difficult to manage as compared with an overdose of ibuprofen. There is clearly a need for advanced studies to investigate the safety of these medications in paediatric populations of different ages and especially during prolonged use. Finally, the recently reported association between frequency and severity of asthma and paracetamol use needs urgent additional investigations.

Determinants of variability in clearance of exogenous compounds in neonates.

Although the general principles of disposition and elimination of exogenous compounds apply in neonates, their specific characteristics warrant a tailored approach. Children display maturation in drug disposition, and these maturational changes are most prominent in the first year of life. Elimination clearance is mainly either through metabolic or renal elimination clearance. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetics factors. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. The impact of various covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite this overall low clearance, interindividual variability is already extensive and can be explained by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor or growth restriction. These findings are illustrated by observations on amikacin, vancomycin and cefazolin disposition in perinatal life. These maturational changes all have impact on the pharmaco/toxicokinetics and -dynamics. We hereby would like to extent the adagio of Paracelsus that 'all is toxic, it only depends on the dose' by making the point that the 'patient' is also relevant.

Developmental pharmacology: neonates are not just small adults...

Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg 0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo 'case' studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in 'generic physiologically-based pharmacokinetic' models.

Covariates of tramadol disposition in the first months of life.

BACKGROUND: Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. METHODS: A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. RESULTS: In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. CONCLUSIONS: Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants.

BACKGROUND: The safety and value of acetaminophen (paracetamol) in addition to continuous morphine infusion has never been studied in newborns and young infants. We investigated the addition of acetaminophen to evaluate whether it decreased morphine consumption in this age group after major thoracic (non-cardiac) or abdominal surgery. METHODS: A randomized controlled trial was performed in 71 patients given either acetaminophen 90-100 mg kg(-1) day(-1)or placebo rectally, in addition to a morphine loading dose of 100 microg kg(-1) and 5-10 microg kg(-1) h(-1) continuous infusion. Analgesic efficacy was assessed using Visual Analogue Scale (VAS) and COMFORT scores. Extra morphine was administered if VAS was > or = 4. RESULTS: We analysed data of 54 patients, of whom 29 received acetaminophen and 25 received placebo. Median (25-75th percentile) age was 0 (0-2) months. Additional morphine bolus requirements and increases in continuous morphine infusion were similar in both groups (P = 0.366 and P = 0.06, respectively). There was no significant difference in total morphine consumption, respectively, 7.91 (6.59-14.02) and 7.19 (5.45-12.06) mug kg(-1) h(-1) for the acetaminophen and placebo group (P = 0.60). COMFORT [median (25-75th percentile) acetaminophen 10 (9-12) and placebo 11 (9-13)] and VAS [median (25-75th percentile) acetaminophen 0.0 (0.0-0.2) and placebo 0.0 (0.0-0.3)] scores did not differ between acetaminophen and placebo group (P = 0.06 and P = 0.73, respectively). CONCLUSIONS: Acetaminophen, as an adjuvant to continuous morphine infusion, does not have an additional analgesic effect and should not be considered as standard of care in young infants, 0-2 months of age, after major thoracic (non-cardiac) or abdominal surgery.

Life threatening central nervous system manifestations and hypothermia due to maneb intoxication in a child: a case report.

Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse. They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure).A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5 degrees C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.

Maturational changes in the in vivo activity of CYP3A4 in the first months of life.

OBJECTIVE: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. METHODS: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. RESULTS: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. CONCLUSIONS: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.

Morphine in ventilated neonates: its effects on arterial blood pressure.

OBJECTIVE: To study the effects of continuous morphine infusion on arterial blood pressure in ventilated neonates. DESIGN: Blinded randomised placebo controlled trial. SETTING: Level III neonatal intensive care unit in two centres. PATIENTS: A total of 144 ventilated neonates. Inclusion criteria were postnatal age <3 days, ventilation <8 hours, and indwelling arterial line. Exclusion criteria were severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers. INTERVENTION: Arterial blood pressure was measured before the start and during the first 48 hours of masked infusion of drug (morphine/placebo; 100 microg/kg + 10 microg/kg/h). OUTCOME MEASURES: Arterial blood pressure and blood pressure variability. RESULTS: There were no significant differences in overall mean arterial blood pressure between the morphine group (median (interquartile range) 36 mm Hg (6) and the placebo group (38 mm Hg (6)) (p = 0.11). Although significantly more morphine treated patients (70%) showed hypotension than the placebo group (47%) (p = 0.004), the use of volume expanders and vasopressor drugs was not significantly different (morphine group, 44%; placebo group, 48%; p = 0.87), indicating the limited clinical significance of this side effect. Blood pressure variability was not influenced by routine morphine analgesia (p = 0.81) or additional morphine (p = 0.80). Patients with and without intraventricular haemorrhage showed no differences in blood pressure (Mann-Whitney U test 1953; p = 0.14) or incidence of hypotension (chi(2) test 1.16; df 1; p = 0.28). CONCLUSIONS: Overall arterial blood pressure, use of inotropes, and blood pressure variability were not influenced by morphine infusion. Therefore the clinical impact of hypotension as a side effect of low dose morphine treatment in neonates is negligible.

O-demethylation of tramadol in the first months of life.

OBJECTIVE: Assess in vivo O-demethylation activity in the first months of life. METHODS: Time-concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated. RESULTS: Plasma samples were available in 20/29 and complete 24-h urine collections were available in 25/29 neonates (25-53 weeks PMA). Mean plasma log M/M1 value (>4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=-0.73, P<0.0001) and PNA (r=-0.58, P<0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=-0.73, P<0.0001) and PNA (r=-0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1 ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12-16 weeks without plateau. CONCLUSIONS: O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates.