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Background and objectives: Selection of the first-dose-in-neonates is challenging. The objective of this proof-of-concept study was to evaluate a pharmacokinetic bridging approach to predict a neonatal dosing regimen. Methods: We selected fluconazole as a paradigm compound. We used data from studies in juvenile mice and adults to develop population pharmacokinetic models using NONMEM. We also develop a physiologically-based pharmacokinetic model from in vitro-in silico data using Simcyp. These three models were then used to predict neonatal pharmacokinetics and dosing regimens for fluconazole. Results: From juvenile mice to neonates, a correction factor of maximum lifespan potential should be used for extrapolation, while a 'renal factor' taking into account renal maturation was required for successful bridging based on adult and in vitro-in silico data. Simulations results demonstrated that the predicted drug exposure based on bridging approach was comparable to the observed value in neonates. The prediction errors were −2.2, +10.1 and −4.6 % for juvenile mice, adults and in vitro-in silico data, respectively. Conclusion: A model-based bridging approach provided consistent predictions of fluconazole pharmacokinetic parameters in neonates and demonstrated the feasibility of this approach to justify the first-dose-in-neonates, based on all data available from different sources (including physiological informations, preclinical studies and adult data), allowing evidence-based decisions of neonatal dose rather than empiricism. [ABSTRACT FROM AUTHOR]

Background: Children are in a continuous and dynamically changing state of growth and development. A thorough understanding of developmental pharmacokinetics (PK) and pharmacodynamics (PD) is required to optimize drug therapy in children. Data sources: Based on recent publications and the experience of our group, we present an outline on integrating pharmacometrics in pediatric clinical practice to develop evidence-based personalized pharmacotherapy. Results: Antibiotics in septic neonates and immunosuppressants in pediatric transplant recipients are provided as proof-of-concept to demonstrate the utility of pharmacometrics in clinical practice. Dosage individualization based on developmental PK-PD model has potential benefits of improving the efficacy and safety of drug therapy in children. Conclusion: The pharmacometric technique should be better developed and used in clinical practice to personalize drug therapy in children in order to decrease variability of drug exposure and associated risks of overdose or underdose. [ABSTRACT FROM AUTHOR]

Aim Lamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and Cmax). Methods Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building. Results A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance ( CL) and volume of distribution ( V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h−1 and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg−1 ranged from 4.44 mg l−1 h for children <14 kg to 7.25 mg l−1 h for children >30 kg. Conclusions The use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered. [ABSTRACT FROM AUTHOR]

Aim Little attention has been paid to the effects of compliance and prescription practice on treatment outcome in HIV-infected children. In this context, an evaluation of the role of covariates on pharmacokinetics is required to establish the impact of differences in dosing regimens. Here we investigate whether a once daily dosing regimen of lamivudine provides comparable exposure to the currently approved paediatric regimen. Methods A hypothetical group of 180 patients between 3 months and 12 years old was used to evaluate the impact of body weight on systemic exposure to lamivudine. Simulation scenarios were evaluated using AUC and Cmax as parameters of interest. The analysis was performed using a population pharmacokinetic model previously implemented in nonmem v.6.2. Results The simulations show that once daily dosing of lamivudine yields comparable exposure to historical values observed in children and adults, both for liquid and solid dosage forms. Simulated steady-state AUC(0-24 h) and Cmax values after once daily doses ranged respectively from 9.95 mg l−1 h and 1.9 mg l−1 for children lighter than 14 kg to 13.75 mg l−1 h and 3.0 mg l−1 for children heavier than 30 kg. These values are comparable or higher than historical values observed after once daily dosing in children and adults. Conclusions Our findings illustrate how dosing regimens can be evaluated taking into account the effects of developmental growth on drug disposition. Most importantly, they suggest that the reduction in dosing frequency to once daily leads to comparable lamivudine exposure, as observed after administration of a twice daily dosing regimen. [ABSTRACT FROM AUTHOR]

Background and Objective: Amikacin clearance has recently been proposed as a marker of renal maturation in neonates. However, the predictive value of this marker is still unknown. The objective of the present exploratory study was to evaluate the predictive performance of renal maturation model derived from amikacin to predict the glomerular filtration rate (GFR) and vancomycin clearance in neonates. Methods: The GFR and vancomycin clearance in neonates were predicted using a maturation model derived from amikacin via estimation and simulation in a cohort of 116 neonates using non-linear mixed–effects modeling NONMEM ® software. Results: Our results demonstrate good correlations between predicted and observed GFR and vancomycin clearance in neonates. The square of the correlation coefficient, and means of the prediction error (2.5th–97.5th percentiles) and absolute prediction error (2.5th–97.5th percentiles) are 0.96, 1.2 % (−39.7 to 30.0 %) and 12.3 % (0.4–39.7 %), respectively, for GFR, and 0.97, −11.3 % (−38.2 to 15.4 %) and 14.0 % (0.5–38.2 %), respectively, for vancomycin. The prediction error is not significantly correlated with age. Conclusion: An amikacin maturation model can precisely reflect maturation of glomerular filtration and thus predict the dosage regimens of other renally excreted drugs by glomerular filtration in neonates. [ABSTRACT FROM AUTHOR]

Aims Antibiotics are a key resource for the management of infectious diseases in neonatology and their evaluation is particularly challenging. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials on antibiotics in neonatal infections. Methods We performed a systematic search of Pub Med, Embase and the Cochrane Library from January 1995 to March 2010. Bibliographies of relevant articles were also hand-searched. We included all randomized controlled trials that involved neonates and evaluated the use of an antibiotic agent in the context of a neonatal infectious disease. Methodological quality was evaluated using the Jadad scale and the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality. Results A total of 35 randomized controlled trials were evaluated. The majority were conducted in a single hospital institution, without funding. Median sample size was 63 (34-103) participants. The most frequently evaluated antibiotic was gentamicin. Respectively, 18 (51%) and 17 (49%) trials evaluated the therapeutic or prophylactic use of antibiotics in various neonatal infections. Overall, the methodological quality was poor and did not improve over the years. Risk of bias was high in 66% of the trials. Conclusions Design and reporting of randomized controlled trials of antibacterial agents in neonates should be improved. Nevertheless, the necessity of implementing such trials when antibacterial efficacy has already been established in other age groups may be questioned and different methods of evaluation should be further developed. [ABSTRACT FROM AUTHOR]

Background and objective: Major changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26 weeks gestational age (GA) to adults. Methods: Pharmacokinetic data after intravenous administration of midazolam were obtained from six previously reported studies. Subjects were premature neonates ( n = 24; GA 26-33.5 weeks, postnatal age (PNA) 3-11 days, and n = 24; GA 26-37 weeks, PNA 0-1 days), 23 children after elective major craniofacial surgery (age 3-23 months), 18 pediatric intensive-care patients (age 2 days-17 years), 18 pediatric oncology patients (age 3-16 years), and 20 healthy male adults (age 20-31 years). Population pharmacokinetic modeling with systematic covariate analysis was performed by use of NONMEM v6.2. Results: Across the entire lifespan from premature neonates to adults, bodyweight was a significant covariate for midazolam clearance. The effect of bodyweight was best described by use of an allometric equation with an exponent changing with bodyweight in an exponential manner from 0.84 for preterm neonates (0.77 kg) to 0.44 for adults (89 kg), showing that the most rapid maturation occurs during the youngest age range. Conclusions: An in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models. [ABSTRACT FROM AUTHOR]

Aims To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations. Methods Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children ( n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg−1 day−1 or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria. Results A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration-time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l−1 and 6.1 mg h l−1 for toddlers and infants, and 3.6 mg l−1 and 8.7 mg h l−1 for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling. Conclusions The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny. [ABSTRACT FROM AUTHOR]

Purpose: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. Methods: A search of EMBASE (1950-January 2012), MEDLINE (1946-January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982-2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients' exposure to fluconazole were included. Results: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87-2.14, P = 0.175 and RR 1.43, 95 % CI 0.67-3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12-5.60, P = 0.831 and RR 1.23, 95 %CI 0.87-1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. Conclusion: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity. [ABSTRACT FROM AUTHOR]

Objective Because pharmacokinetic data are limited, continuous infusions of vancomycin in neonates are administered using different dosing regimens. The aim of this work was to evaluate the results of vancomycin therapeutic drug monitoring (TDM) under three different dosing regimens and to optimise vancomycin therapy. Methods Vancomycin TDM concentrations were noted and compared prospectively in three hospitals. Population pharmacokinetic analysis was performed to optimise dosing using NONMEM software. Patienttailored optimised dosing regimens were evaluated in a prospective study. Results Two hundred and seven serum vancomycin concentrations from 116 neonates were analysed. Only 48 neonates (41%) had serum vancomycin concentrations within the therapeutic range of 15-25 mg/l using a current dosing regimen. Concentrations ranged from 5.1 to 61.5 mg/l. Loading doses were required to decrease the risk of subtherapeutic levels during early treatment. An optimised dosing regimen, taking into account birth weight, current weight, postnatal age and serum creatinine, was developed based on a one-compartment pharmacokinetic model. A prospective validation study in 58 neonates demonstrated a higher percentage of neonates (70.7%, n=41) reaching the therapeutic range and early dosage adaptation (6-12 h post-dose) using an optimised dosing regimen. Conclusions A patient-tailored optimised dosing regimen should be used routinely to individualise vancomycin continuous infusion therapy in neonates. [ABSTRACT FROM AUTHOR]

Background: A limited sampling strategy (LSS) for estimating the area under the curve (AUC) of the prolonged-release formulation of tacrolimus (tacrolimus) is not available in pediatric patients, although the method is of real benefit to children. The objective of this study was to develop and validate a reliable and clinically applicable LSS using Bayesian estimation for estimating tacrolimus AUC in pediatric kidney transplant patients Methods: The original tacrolimus pharmacokinetic dataset consisted of 22 full profiles from 22 pediatric kidney transplant patients. The Bayesian estimation method was used to develop the LSS. External validation was performed in an independent validation group which consisted of 20 full pharmacokinetic profiles from 12 pediatric kidney transplant patients. Results: Bayesian estimator using C C and C gave the best predictive performance with a mean prediction error of 2.2 % in the external validation dataset. There was no correlation between the prediction error and age. The Bland-Altman analysis showed that the mean difference between the reference and Bayesian-estimated AUC was 3.5 (95 % confidence interval −3.5-10.5) ng h/mL Conclusions: A reliable and clinically applicable LSS for estimating AUC of tacrolimus was determined and validated in children. The prediction was unbiased and precise. It can be used as a routine procedure to perform AUC-based tacrolimus dosage optimization in pediatric renal transplant patients. [ABSTRACT FROM AUTHOR]

Aims Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. Method Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check ( VPC) and normalized prediction distribution errors ( NPDE)]. Results Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. Conclusion The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin. [ABSTRACT FROM AUTHOR]

Purpose: To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area. Methods: The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs. Results: A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin. Conclusions: Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres' interest in off-patent medicine research. [ABSTRACT FROM AUTHOR]

Background and Objectives: Tacrolimus is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus pharmacokinetics, including CYP3A5 polymorphism. Methods: Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. Results: The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2 ± 10.1 vs. 53.5 ± 20.2 L/h, p = 0.01). Conclusions: The population pharmacokinetic model of tacrolimus was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus dosing regimen in routine clinical practice. [ABSTRACT FROM AUTHOR]

Neonatal sepsis causes a huge burden of morbidity and mortality and includes bloodstream, urine, cerebrospinal, peritoneal, and lung infections as well as infections starting from burns and wounds, or from any other usually sterile sites. It is associated with cytokine - and biomediator-induced disorders of respiratory, hemodynamic, and metabolic processes. Neonates in the neonatal intensive care unit feature many specific risk factors for bacterial and fungal sepsis. Loss of gut commensals such as Bifidobacteria and Lactobacilli spp., as occurs with prolonged antibiotic treatments, delayed enteral feeding, or nursing in incubators, translates into proliferation of pathogenic microflora and abnormal gut colonization. Prompt diagnosis and effective treatment do not protect septic neonates form the risk of late neurodevelopmental impairment in the survivors. Thus prevention of bacterial and fungal infection is crucial in these settings of unique patients. In this view, improving neonatal management is a key step, and this includes promotion of breast-feeding and hygiene measures, adoption of a cautious central venous catheter policy, enhancement of the enteric microbiota composition with the supplementation of probiotics, and medical stewardship concerning H2 blockers with restriction of their use. Additional measures may include the use of lactoferrin, fluconazole, and nystatin and specific measures to prevent ventilator associated pneumonia. [ABSTRACT FROM AUTHOR]

Background: The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability. Aim: This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL. [ABSTRACT FROM AUTHOR]

Idiopathic nephrotic syndrome (INS) has been studied for decades in attempt to understand the physiopathological mechanisms explaining the disease. It is recognized as a multifactorial disease, with immunological components targeting kidney functions. Many hypotheses have been discussed or tested, including the role of a circulating factor, polymorphisms of genes implicated in lymphocyte maturation and differentiation, and DNA epigenetic modifications. In the present review, the data supporting these different (and probably combinatorial) hypotheses have been reviewed in order to identify and discuss the possible pathways implicated in the physiopathology of INS. [ABSTRACT FROM AUTHOR]

Chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in preterm infants. Ureaplasma has received intermittent attention over the last two decades as a possible contributory factor. In addition, pulmonary inflammation is associated with the development of CLD. The macrolide azithromycin provides an attractive option to determine if it can decrease the development of CLD as it has both anti-inflammatory and anti-infective properties. In this article, the authors review the evidence for the role of Ureaplasma in the development of CLD and the obstacles faced in the development of a drug before it reaches clinical practice. [ABSTRACT FROM AUTHOR]

This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines. Even though regulatory authorities may be aware of the potential role of PG in medical practice and guidances are available about the integration of PG in drug development, most data obtained from PG studies are not used by prescribers. The challenge is to better understand whether PG markers can be used to assess potential differences in drug response during the clinical program, so PG data can be integrated into the regulatory decision-making process, enabling the introduction of labeling information that promotes optimal dosing in the pediatric population. [ABSTRACT FROM PUBLISHER]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily. • Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. WHAT THIS STUDY ADDS • A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. • Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. • A maximum a posteriori probability Bayesian estimator of AUC0- t based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers. AIMS To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0- t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0- t was developed from the final model and can be used routinely to optimize individual dosing. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m e.o.d ( p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m/month ( p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide. [ABSTRACT FROM AUTHOR]

Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies. Conclusions: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis. [ABSTRACT FROM AUTHOR]

The burden of neonatal invasive Candida infection (ICI) has been increasing recently and identification of effective preventative and treatment strategies is a priority. In this view, the echinocandin class of antifungal agents has emerged as a suitable and promising option for treatment. These agents have overall characteristics that suitably meet the needs of neonatal patients, such as coverage against biofilms and against fluconazole-resistant strains of Candida spp, which is an issue in an epoch of increasing prophylactic use of fluconazole in the nursery. Micafungin is the only echinocandin authorized for neonatal use by the EMA, based on efficacy and PK data from neonatal populations. Although the kinetics and appropriate dosing of this agent in premature and term infants have been described in the recent years, through either neonatal studies or extrapolation form adult data, further studies are needed to better address this area. These studies should be properly designed for neonatal populations, and must better address long-term safety and the clinical outcomes related to echinocandin use in neonates. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In paediatric development, initial estimation of the paediatric dose is obtained by extrapolation. This is usually performed using the dosing regimen in another population as reference. However, no consensus on dose selection methodologies has been reached so far. • The paradigm compound identified to illustrate these concepts is a nucleoside reverse transcriptase inhibitor (NRTI) used to treat HIV infection. The recommended paediatric dose of abacavir is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily. WHAT THIS STUDY ADDS • Our findings show that the use of a population model may not suffice to predict parameter distributions and drug exposure across paediatric populations. • Estimation of covariate effects is critical, but not sufficient to extrapolate pharmacokinetics from a reference population to another population. • Covariate-parameter correlations may not remain constant beyond the range of observations. Exponential relationships used by allometry do not correct for these discrepancies. AIMS To assess the predictive value of a model-based approach for dose selection across paediatric populations in early clinical drug development. METHODS Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around. RESULTS The pharmacokinetic models (a two-compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%-CI) was estimated at 7.03 (6.72, 7.48) µg ml−1 h, whilst it was predicted at 5.75 (4.82, 6.26) µg ml−1 h; in children, the estimated median AUC was 6.96 (5.85, 7.91) µg ml−1 h, whilst the predicted value was 6.45 (5.80, 7.01) µg ml−1 h. CONCLUSIONS These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations. [ABSTRACT FROM AUTHOR]

Objective To determine the safety of ciprofloxacin in paediatric patients in relation to arthropathy, any other adverse events (AEs) and drug interactions. Methods A systematic search of MEDLINE, EMBASE, CINAHL, CENTRAL and bibliographies of relevant articles was carried out for all published articles, regardless of design, that involved the use of ciprofloxacin in any paediatric age group ⩽17 years. Only articles that reported on safety were included. Results 105 articles met the inclusion criteria and involved 16 184 paediatric patients. There were 1065 reported AEs (risk 7%, 95% CI 3.2% to 14.0%). The most frequent AEs were musculoskeletal AEs, abnormal liver function tests, nausea, changes in white blood cell counts and vomiting. There were six drug interactions (with aminophylline (4) and methotrexate (2)). The only drug related death occurred in a neonate who had an anaphylactic reaction. 258 musculoskeletal events occurred in 232 paediatric patients (risk 1.6%, 95% CI 0.9% to 2.6%). Arthralgia accounted for 50% of these. The age of occurrence of arthropathy ranged from 7 months to 17 years (median 10 years). All cases of arthropathy resolved or improved with management. One prospective controlled study estimated the risk of arthropathy as 9.3 (OR 95% CI 1.2 to 195). Pooled safety data of controlled trials in this review estimated the risk of arthropathy as 1.57 (OR 95% CI 1.26 to 1.97). Conclusion Musculoskeletal AEs occur due to ciprofloxacin use. However, these musculoskeletal events are reversible with management. It is recommended that further prospective controlled studies should be carried out to evaluate the safety of ciprofloxacin, with particular focus on the risk of arthropathy. [ABSTRACT FROM AUTHOR]

There are many limitations to conducting pharmacokinetic studies in neonates, both ethical and technical. Regarding technical aspects, the number and volume of samples are limited, and the analytical method to measure drug concentration should be both specific and highly sensitive. In the present report, an analytical method adapted to neonates was developed for the determination of ciprofloxacin plasma concentration. After a simple protein precipitation, analytes were separated on a micro-liquid chromatography and quantified by mass spectrometry, with D8-ciprofloxacin as internal standard. The calibration range was linear from 25 to 3000 ng/mL. Intra- and inter-day precision was less than 2.4 and 4.1%, respectively. The acceptance criteria of accuracy (between 85 and 115%) were met in all cases. A plasma volume of 150 µL was required to achieve the limit of quantification of 25 ng/mL. The method was successfully applied to routine monitoring of ciprofloxacin in pediatric patients and also used in preclinical studies. It will be used to determine the population pharmacokinetic parameters of ciprofloxacin in neonates. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

• The pharmacogenetic polymorphisms of both TPMT and ITPA are associated with individual variability in 6-mercaptopurine (6-MP) intracellular metabolism. • The balance between red blood cell (RBC) 6-thioguanine nucleotide (6TGN) and 6-methylated metabolite (6-MMPN) concentrations has an important impact on efficacy in children treated for acute lymphoblastic leukemia. • Hepatotoxicity is a frequent complication of the association 6-MP and methotrexate during maintenance therapy. • RBC 6-TGN concentrations are dependant on TPMT genotype and age, while RBC 6-MMPN concentrations depend on TPMT and ITPA polymorphisms. • Children aged 6 years or less had lower RBC 6-TGN concentrations during maintenance therapy, demonstrating an age effect on 6-MP intracellular metabolism. • Hepatotoxicity is a frequent complication of the association of 6-MP and methotrexate. A 6-MMPN threshold of 5000 pmol/8 × 10 RBC was associated with an increased risk of hepatotoxicity. 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase ( TPMT) and inosine triphosphate pyrophosphatase ( ITPA) on 6-MP metabolism and response. Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+ 21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10RBC) than in older children (600 pmol/8 × 10RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10RBC was associated with an increased risk of hepatotoxicity. In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children. [ABSTRACT FROM AUTHOR]

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS • The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time. • Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed. AIMS To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration–time curve over 12 h (AUC0–12). METHODS The pharmacokinetic model of MMF was described from 23 patients aged 7.4 ± 3.9 years (range 2.9–14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag–time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTS The population pharmacokinetic parameters were apparent oral clearance 9.7 l h−1, apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h−1, absorption rate constant 5.16 h−1, lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC0–12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 µg h−1 ml−1 between estimated and reference AUC0–12. CONCLUSIONS The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing. [ABSTRACT FROM AUTHOR]

Background and objective: A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug. Methods: A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM® V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors. Results: Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight. Conclusions: Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in μg/kg and a maintenance dose expressed in μg/kg1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made. [ABSTRACT FROM AUTHOR]