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There was a mistake in the units of CL and Q, and in the parentheses of the formula for CL in the final model in Table 2. The corrected Table appears below.

Glomerular filtration (GF) and active tubular secretion (ATS) contribute to renal drug elimination, with the latter remaining understudied across the pediatric age range. Therefore, we systematically analyzed the influence of transporter ontogeny on the relative contribution of GF and ATS to renal clearance CLR for drugs with different properties in children. A physiology-based model for CLR in adults was extrapolated to the pediatric population by including maturation functions for the system-specific parameters. This model was used to predict GF and ATS for hy

Introduction: Current drug dosing in preterm infants is standardized, mostly based on bodyweight. Still, covariates such as gestational and postnatal age may importantly alter pharmacokinetics and pharmacodynamics. Evaluation of drug therapy in these patients is very difficult because objective pharmacodynamic parameters are generally lacking. By integrating continuous physiological data with model-based drug exposure and data on adverse drug reactions (ADRs), we aimed to show the potential benefit for optimized individual pharmacotherapy. Materials and Methods: Continuous data on oxygen saturation (SpO2), fraction of inspired oxygen (FiO2) and composite parameters, including the SpO2/FiO2 ratio and the cumulative oxygen shortage under the 89% SpO2 limit, served as indicators for doxapram effectiveness. We analyzed these continuous effect data, integrated with doxapram exposure and ADR parameters, obtained in preterm infants around the start of doxapram therapy. The exposures to doxapram and the active metabolite keto-doxapram were simulated using a population pharmacokinetic model. Infants were selected and retrospectively compared on the indication to start doxapram, the first response to doxapram, a potential dose-response relationship, and the administered dosage over time. Recommendations were made for individual improvements of therapy. Results: We provide eight cases of continuous doxapram administration that illustrate a correct and incorrect indication to start doxapram, responders and non-responders to therapy, and unnecessary over-exposure with ADRs. Recommendations for improvement of therapy include: objective evaluation of added effect of doxapram after start, prevention of overdosing by earlier down-titration or termination of therapy, and the prevention of hypoxia and agitation by measuring specific parameters at strategical time-points. Conclusion: Real-time and non-invasive effect monitoring of drug therapy combined with model-based exposure provide

Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after ca

Aims: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400–700 mg h L−1). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. Methods: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0–234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg−1, maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11–13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60–230 kg) were performed using NONMEM. Results: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg−1 day−1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L−1) in individuals up to 200 kg, with corresponding trough concentrations of 5.7–14.6 mg L−1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for st

BACKGROUND: The clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term. OBJECTIVE: The current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing. DESIGN: A single-blind, randomised controlled trial. SETTING: A t

To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonat

Purpose: Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint,u,WL) and hepatic blood flow (Qh) in children. Methods: First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation. Results: Precise estimation of CLint,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER) ≤ 0.27 and the other has an ER ≥ 0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty. Conclusion: The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.

Purpose: Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods: Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1–18 years of age after oral administration were analyzed using a physiological population PK modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results: The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5–405) times lower intrinsic gut wall clearance than the intrinsic hepatic clearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8–50.0%). Conclusion: In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

Purpose: Ibuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge. Methods: We performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure. Results: The most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg−1 followed by 10 mg kg−1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L−1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg−1, followed by 4 mg kg−1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg−1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower. Conclusions: We propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.

Background: In view of the increased use of metformin in obese adolescents, the aim of this study was to determine the pharmacokinetics of metformin in overweight and obese adolescents. Methods: In overweight and obese adolescents receiving metformin 500 or 1000 mg twice daily for 37 weeks during a clinical trial, blood samples were collected over 8 h during an oral glucose tolerance test. Population pharmacokinetic modeling was performed using NONMEM. Results: Data for 22 overweight and obese adolescents with a mean total body weight (TBW) of 79.3 kg (range 54.7–104.9), body mass index (BMI) of 29.1 kg/m2 (range 22.9–39.3), and age of 15.9 years (range 11.1–17.5) were analysed. In the model, oral clearance (CL/F) of metformin (1.17 l/min [relative standard error of 6%]) increased significantly with TBW (p < 0.01). More specifically, CL/F increased with both developmental weight (WTfor age and length) and excess body weight (WTexcess), for which an excess weight covariate model was proposed. Conclusion: The CL/F of metformin in obese adolescents (1.17 l/min) is larger than that in non-obese children (0.55 l/min) and similar to that in adults (1.3 l/min) as reported in the literature. This increase may potentially be explained by increased tubular secretion of metformin. These results appear to indicate that adult dosages of metformin could be considered in obese adolescents if pediatric dosages have been therapeutically ineffective.

Objective: This review addresses sedation management on paediatric intensive care units and possible gaps in the knowledge of optimal sedation strategies. We present an overview of the commonly used sedatives and their pharmacokinetic and pharmacodynamic considerations in children, as well as the ongoing studies in this field. Also, sedation guidelines and current sedation strategies and assessment methods are addressed. Key findings: This review shows that evidence and pharmacokinetic data are scarce, but fortunately, there is an active research scene with promising new PK and PD data of sedatives in children using new study designs with application of advanced laboratory methods and modelling. The l

Introduction: Pharmacologic pain management in newborns and infants is often based on limited scientific data. To close the knowledge gap, drug-related research in this population is increasingly supported by the authorities, but remains very challenging. This review summarizes the challenges of analgesic studies in newborns and infants on morphine and paracetamol (acetaminophen). Areas covered: Aspects such as the definition and multimodal character of pain are reflected to newborn infants. Specific problems addressed include defining pharmacodynamic endpoints, performing clinical trials in this population and assessing developmental changes in both pharmacokinetics and pharmacodynamics. Expert commentary: Neonatal and infant pain management research faces two major challenges: lack of clear biomarkers and very heterogeneous pharmacokinetics and pharmacodynamics of analgesics. There is a clear call for integral research addressing the multimodality of pain in this population and further developing population pharmacokinetic models towards physiology-based models.

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.

The majority of marketed drugs remain understudied in some patient populations such as pregnant women, paediatrics, the obese, the critically-ill, and the elderly. As a consequence, currently used dosing regimens may not assure optimal efficacy or minimal toxicity in these patients. Given the vulnerability of some subpopulations and the challenges and costs of performing clinical studies in these populations, cutting-edge approaches are needed to effectively develop evidence-based and individualized drug dosing regimens. Five key issues are presented that are essential to support and expedite the development of drug dosing regimens in these populations using model-based approaches: 1) model development combined with proper validation procedures to extract as much valid information from available study data as possible, with limited burden to patients and costs; 2) integration of existing data and the use of prior pharmacological and physiological knowledge in study design and data analysis, to further develop knowledge and avoid unnecessary or unrealistic (large) studies in vulnerable populations; 3) clinical proof-of-principle in a prospective evaluation of a developed drug dosing regimen, to confirm that a newly proposed regimen indeed results in the desired outcomes in terms of drug concentrations, efficacy, and/or safety; 4) pharmacodynamics studies in addition to pharmacokinetics studies for drugs for which a difference in disease progression and/or in exposure-response relation is anticipated compared to the reference population; 5) additional efforts to implement developed dosing regimens in clinical practice once drug pharmacokinetics and pharmacodynamics have been characterized in special patient populations. The latter remains an important bottleneck, but this is essential to truly realize evidence-based and individualized drug dosing for special patient populations. As all tools required for this purpose are available, we have the moral and societal oblig

Background: We previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP). Methods: Infants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolite

Pain is a complex biopsychosocial phenomenon of which the intensity, location and duration depends on various underlying components. Treatment of pain is associated with considerable inter-individual variability, and as such, requires a personalized approach. However, a priori prediction of optimal analgesic treatment for individual patients is still challenging. Another challenge is the assessment and treatment of pain in patients unable to self-report pain. In this mini-review, we first provide a brief overview of the various components underlying pain, and their associated biomarkers. These include clinical, psychosocial, neurophysiological, and biochemical components. We then discuss the use of empirical and mechanism-based pharmacokinetic-pharmacodynamic modelling to support personalized treatment of pain. Finally, we propose how these concepts can be extended to a quantitative systems pharmacology (QSP) approach that integrates the components of clinical pain and treatment response. This integrative approach can support predictions of optimal pharmacotherapy of pain, compared with approaches that focus on single components of pain. Moreover, combination of QSP modelling with state-of-the-art metabolomics approaches may offer unique possibilities to identify novel pain biomarkers. Such biomarkers could support both the personalized treatment of pain and translational drug development of novel analgesic agents. In conclusion, a QSP approach will likely improve our ability to predict pain and treatment response, paving the way for personalized treatment of pain.

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Background The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. Methods Data from 19 obese adolescents [102.7 kg (62–149.5 kg)] and 20 morbidly obese adults [144 kg (112–186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW − WTfor age and length) was evaluated. Results The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called ‘excess weight’ model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed. Discussion We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.

The gold standard for quantification of pain is a person's self-report. However, we need objective parameters for pain measurement when intensive care patients, for example, are not able to report pain themselves. An increase in pain is currently thought to coincide with an increase in stress hormones. This observational study investigated whether procedure-related pain is associated with an increase of plasma cortisol, adrenaline, and noradrenaline. In 59 patients receiving intensive care after cardiac surgery, cortisol, adrenaline, and noradrenaline plasma levels were measured immediately before and immediately after patients were turned for washing, either combined with the removal of chest tubes or not. Numeric rating scale scores were obtained before, during, and after the procedure. Unacceptably severe pain (numeric rating scale ≥ 4) was reported by seven (12%), 26 (44%), and nine (15%) patients, before, during and after the procedure, respectively. There was no statistically significant association between numeric rating scale scores and change in cortisol, adrenaline, and noradrenaline plasma levels during the procedure. Despite current convictions that pain coincides with an increase in stress hormones, procedural pain was not associated with a significant increase in plasma stress hormone levels in patients who had undergone cardiac surgery. Thus, plasma levels of cortisol, adrenaline, and noradrenaline seem unsuitable for further research on the measurement of procedural pain.

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Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug–drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children.

Purpose: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. Methods: In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient’s sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the ‘open’ infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat. Results: From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6–25.8) versus PS 24.0 days (IQR 20.6–26.0); median difference 0.02 days (95 % CI −0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2–11.0) versus PS 7.4 days (IQR 5.3–12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6–26.7) versus PS 15.7 days (IQR 9.3–33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6–22.6) versus PS 17.0 mg/kg (IQR 8.2–39.8), p = 0.11. Conclusion: In

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results: In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC0–8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pa

Important information gaps remain on the efficacy and safety of drugs in children. Pediatric drug development encounters several ethical, practical, and scientific challenges. One barrier to the evaluation of medicines for children is a lack of innovative methodologies that have been adapted to the needs of children. This article presents our successful experience of pediatric microdose and microtracer studies using 14C-labeled probes in Europe to illustrate the strengths and limitations of these approaches.

Aim In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents. Methods Overweight (BMI for age ≥ 85th percentile) and obe

Purpose: Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach. Methods: A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses. Results: Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg1.4, which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both meta

Objectives: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. Methods: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. Results: Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. Conclusions: The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.

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.

Aim The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. Methods A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. Results In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). Conclusions Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

Background: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and e

Results: Ten infants (aged 0.1–83.1 months) were included; one was excluded as he vomited shortly after administration. In nine patients, [14C]AAP and metabolites in blood samples were detectable at expected concentrations: median (range) maximum concentration (Cmax) [14C]AAP 1.68 (0.75–4.76) ng/L, [14C]AAP-Glu 0.88 (0.34–1.55) ng/L, and [14C]AAP-4Sul 0.81 (0.29–2.10) ng/L. Dose-normalized oral [14C]AAP Cmax approached median intravenous average concentrations (Cav): 8.41 mg/L (3.75–23.78 mg/L) and 8.87 mg/L (3.45–12.9 mg/L), respectively.Conclusions: We demonstrate the feasibility of using a [14C]labeled microdose to study AAP pharmacokinetics, including metabolite disposition, in young children.Background: Pediatric drug development is hampered by practical, ethical, and scientific challenges. Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labeled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons.Methods: In an open-label microdose pharmacokinetic pilot study, infants (0–6 years of age) received a single oral [14C]AAP microdose (3.3 ng/kg, 60 Bq/kg) in addition to intravenous therapeutic doses of AAP (15 mg/kg intravenous every 6 h). Blood samples were taken from an indwelling catheter. AAP blood concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and [14C]AAP and metabolites ([14C]AAP-Glu and [14C]AAP-4Sul) were measured by accelerator mass spectrometry.Objective: The objective of this study was to present pilot data of an oral [14C]paracetamol [acetaminophen (AAP)] microdosing study as proof of concept to study developmental pharmacokinetics in children.

Aim For scaling clearance between adults and children, allometric scaling with a fixed exponent of 0.75 is often applied. In this analysis, we performed a systematic study on the allometric exponent for scaling propofol clearance between two subpopulations selected from neonates, infants, toddlers, children, adolescents and adults. Methods Seven propofol studies were included in the analysis (neonates, infants, toddlers, children, adolescents, adults1 and adults2). In a systematic manner, two out of the six study populations were selected resulting in 15 combined datasets. In addition, the data of the seven studies were regrouped into five age groups (FDA Guidance 1998), from which four combined datasets were prepared consisting of one paediatric age group and the adult group. In each of these 19 combined datasets, the allometric scaling exponent for clearance was estimated using population pharmacokinetic modelling (nonmem 7.2). Results The allometric exponent for propofol clearance varied between 1.11 and 2.01 in cases where the neonate dataset was included. When two paediatric datasets were analyzed, the exponent varied between 0.2 and 2.01, while it varied between 0.56 and 0.81 when the adult population and a paediatric dataset except for neonates were selected. Scaling from adults to adolescents, children, infants and neonates resulted in exponents of 0.74, 0.70, 0.60 and 1.11 respectively. Conclusions For scaling clearance, allometric scaling may be of value for scaling between adults and adolescents or children, while it can neither be used for neonates nor for two paediatric populations. For scaling to neonates an exponent between 1 and 2 was identified.

Purpose: To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. Methods: Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. Results: Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. Conclusions: A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight.

BackgroundReports conflict on optimal postoperative analgesic treatment in children with intellectual disability. We retrospectively compared postoperative analgesics consumption between neonates with and without Downs syndrome in relation to anaesthesia requirements and pain scores. MethodsWe analysed hypnotic and analgesic drug administration, pain scores [COMFORT-Behaviour (COMFORT-B) scale], and duration of mechanical ventilation during the first 48 h after surgical repair of congenital duodenal obstruction in neonates, between 1999 and 2011. Data of 15 children with Downs syndrome were compared with data of 30 children without Downs syndrome. ResultsGeneral anaesthesia requirements did not differ. The median (inter-quartile range) maintenance dose of morphine during the first 24 h after operation was 9.5 (7.810.1) g kg -1 h -1 in the Downs syndrome group vs 7.7 (5.010.0) g kg -1 h -1 in the control group (P0.46). Morphine doses at postoperative day 2 and COMFORT-B scores at day 1 did not significantly differ between the two groups. COMFORT-B scores at day two were lower in children with Downs syndrome (P0.04). The duration of postoperative mechanical ventilation did not statistically differ between the two groups (P0.89). ConclusionsIn this study, neonates with and without Downs syndrome received adequate postoperative analgesia, as judged from comparable analgesic consumption and pain scores. We recommend prospective studies in children of different age groups with Downs syndrome and in other groups of intellectually disabled children to provide further investigation of the hypothesis that intellectual disability predisposes to different analgesic requirements.

To develop a maturation function for drug glucuronidation in children, that can be used in population and physiologically based modeling approaches, the physiological and physicochemical basis of a semiphysiological glucuronidation function for children was untangled using Simcyp. The results show that using the currently available in vitro data, in vivo morphine and zidovudine clearances were under predicted by the physiologically based model in Simcyp. The maturation profile was similar to the clinically observed profile except for the first 2 weeks of life, and liver size and UGT2B7 ontogeny are the physiological drivers of the maturation of glucuronidation. Physicochemical drug parameters did not affect this maturation profile, although log P and pKa influenced the absolute value of clearance. The results suggest that the semiphysiological glucuronidation function for young children can be used to predict the developmental clearance profile of other UGT2B7 substrates, though scenarios with nonlinear kinetics and high-extraction ratios require further investigation.

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.

Background: Assessing pain in mechanically ventilated critically ill patients is a great challenge. There is a need for an adequate pain measurement tool for use in conscious sedated patients because of their questionable communicative abilities. In this study, we evaluated the use of the Behavioral Pain Scale (BPS) in conscious sedated patients in comparison with its use in deeply sedated patients, for whom the BPS was developed. Additionally, in conscious sedated patients, the combination of the BPS and the

Background: Pain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU. Methods: We performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients (n = 113). Results: Inter-rater reliability of the NRS and BPS proved to be adequate (kappa = 0.71 and 0.67, respectively). The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS ≥4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found (rs= 0.84, P < 0.001). In ventilated patients, a moderate positive correlation was found between the NRS and the BPS (rs= 0.55, P < 0.001). However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low (median 3.0, range 3.0 to 5.0). Conclusion: The different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (≥4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. In ventilated patients, the BPS should be used only in conjunction with the