Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics.

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers.

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy.

PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

AIMS: Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough ) of MHD (3-35 mg l-1 ). METHODS: A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg l-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg-1  day-1 . RESULTS: A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h-1  70 kg-1 , 337 l 70 kg-1 , 60.7 l and 62.5 l h-1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h-1  70 kg-1 and 54.8 l 70 kg-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg-1  day-1 instead of the recommended target maintenance dose (30-45 mg kg-1  day-1 ) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg-1  day-1 instead of the maximum recommended dose of 60 mg kg-1  day-1 . CONCLUSION: This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.

Enduring large use of acetaminophen suppositories for fever management in children: a national survey of French parents and healthcare professionals' practices.

UNLABELLED: The pharmacological specificities of the rectal formulation of acetaminophen led to a debate on its appropriateness for managing fever in children, but few data are available on the formulation's current use and determinants of use. In a national cross-sectional study between 2007 and 2008, healthcare professionals were asked to include five consecutive patients with acute fever. Among the 6255 children (mean age 4.0 years ± 2.8 SD) who received acetaminophen given by parents or prescribed/recommended by healthcare professionals, determinants of suppository use were studied by multilevel models. A suppository was given by 27 % of parents and prescribed/recommended by 19 % of healthcare professionals, by 24 and 16 %, respectively, for children 2 to 5 years old, and by 13 and 8 %, respectively, for those 6 to 12 years old. Among children who received suppositories from parents and healthcare professionals, 83 and 84 %, respectively, did not vomit. Suppository use was independently associated with several patient- and healthcare professional-level characteristics: young age of children, presence of vomiting, or lack of diarrhea. CONCLUSION: We report an enduring large use of suppositories in France for the symptomatic management of fever in children, including in non-vomiting and/or older children. The rational for such use should be questioned. WHAT IS KNOWN: • The pharmacological specificities of the rectal formulation of acetaminophen have led to a debate on its appropriateness for managing fever in children. Few data are available on the formulation's current use and determinants of the use. What is New: • In a national cross-sectional study, we observed a large use of suppositories in France for symptomatic management of fever in children. Suppositories were frequently used for the youngest children but also for older and/or non-vomiting children.

National cross-sectional study of nonsteroidal anti-inflammatory drugs use highlights differences between parents and professionals and prompts safety concerns.

AIM: Controversy surrounding the safety of nonsteroidal anti-inflammatory drugs (NSAIDs) provides an opportunity to study parents' and healthcare professionals' differential use of over-the-counter drugs. METHODS: In this national cross-sectional study, general practitioners, paediatricians and pharmacists were asked to include up to five consecutive febrile paediatric patients aged 1 month to 12 years. Parents and healthcare professionals completed questionnaires about the current fever episode. We studied the differential use of NSAIDs by parents and healthcare professionals notably in three clinical conditions with various estimated risk of NSAIDs complications: varicella, gastroenteritis and pharyngitis. RESULTS: The 1534 healthcare professionals prescribed 15% of the 6596 children with an NSAID, but 32% of the parents gave their child an NSAID. Generally, NSAID use was associated with older children, higher temperatures, pain due to otitis and the absence of a rash or gastroenteritis. The differential use of NSAIDs by parents and professionals was greater in conditions with high than low estimated risks of NSAID complications, with odds ratios ranging from to 9.0 to 2.9, respectively. CONCLUSION: The differential use of NSAIDs by healthcare professionals and parents for clinical conditions with potential risks should prompt discussions about the safety of their over-the-counter status.

Breast-lesion Segmentation Combining B-Mode and Elastography Ultrasound.

Breast ultrasound (BUS) imaging has become a crucial modality, especially for providing a complementary view when other modalities (i.e., mammography) are not conclusive in the task of assessing lesions. The specificity in cancer detection using BUS imaging is low. These false-positive findings often lead to an increase of unnecessary biopsies. In addition, increasing sensitivity is also challenging given that the presence of artifacts in the B-mode ultrasound (US) images can interfere with lesion detection. To deal with these problems and improve diagnosis accuracy, ultrasound elastography was introduced. This paper validates a novel lesion segmentation framework that takes intensity (B-mode) and strain information into account using a Markov Random Field (MRF) and a Maximum a Posteriori (MAP) approach, by applying it to clinical data. A total of 33 images from two different hospitals are used, composed of 14 cancerous and 19 benign lesions. Results show that combining both the B-mode and strain data in a unique framework improves segmentation results for cancerous lesions (Dice Similarity Coefficient of 0.49 using B-mode, while including strain data reaches 0.70), which are difficult images where the lesions appear with blurred and not well-defined boundaries.

A review of potential pharmacogenetic effects on catecholamine responses.

Considerably, variability in the clinical response to inotropic agents is observed and could be explained partially by the genetic variants, such as single-nucleotide polymorphism (SNP) in genes encoding for enzymes implicated in catecholamines synthesis, metabolism, storage and release or in the signaling pathway. This review highlights the potential effect of pharmacogenetics studies in hemodynamic response and identified 11 SNPs that could be relevant to explain the high variability drug response for a same dose. Cardiovascular instability, such as hypotension, is one of the premature birth complications. The pharmacogenetics studies evaluating these SNP may be useful to better understand the clinical outcome, particularly in this population.

Evaluating lesion segmentation on breast sonography as related to lesion type.

Breast sonography currently provides a complementary diagnosis when other modalities are not conclusive. However, lesion segmentation on sonography is still a challenging problem due to the presence of artifacts. To solve these problems, Markov random fields and maximum a posteriori-based methods are used to estimate a distortion field while identifying regions of similar intensity inhomogeneity. In this study, different initialization approaches were exhaustively evaluated using a database of 212 B-mode breast sonograms and considering the lesion types. Finally, conclusions about the relationship between the segmentation results and lesions types are described.

Pharmacoepidemiology studies: what levels of evidence and how can they be reached?

In pharmacoepidemiology studies, the nature of the research question will dictate the choice of methodological approach and the conditions for optimizing the level of evidence. Thus, to document the treated population and the modes of use of a new drug in real-life prescribing conditions, a descriptive approach through cross-sectional or longitudinal studies conducted on databases, or else ad-hoc studies, will be preferred. On the other hand, evaluation of the real-life "effectiveness" of a new drug will be based on cohort, case-control or scientific modeling, depending on the drug and the disease of interest. For questions involving drug risks and safety, it is the adverse effects profile that will guide the choice of study design, both for identification of the effect (signal) and assessment of causation. In all cases, in the post-marketing authorization (MA) setting, the evidence acquired in pre-MA studies serves as the basis for generating hypotheses. Whatever the research question and the method chosen to address it, the potential biases and their impact on the results need to be identified. In certain cases, a combination of several complementary approaches may prove preferable to a single study.

Multitask, Multilabel, and Multidomain Learning With Convolutional Networks for Emotion Recognition.

Automated emotion recognition in the wild from facial images remains a challenging problem. Although recent advances in deep learning have assumed a significant breakthrough in this topic, strong changes in pose, orientation, and point of view severely harm current approaches. In addition, the acquisition of labeled datasets is costly and the current state-of-the-art deep learning algorithms cannot model all the aforementioned difficulties. In this article, we propose applying a multitask learning loss function to share a common feature representation with other related tasks. Particularly, we show that emotion recognition benefits from jointly learning a model with a detector of facial action units (collective muscle movements). The proposed loss function addresses the problem of learning multiple tasks with heterogeneously labeled data, improving previous multitask approaches. We validate the proposal using three datasets acquired in noncontrolled environments, and an application to predict compound facial emotion expressions.

Pharmacokinetic design optimization in children and estimation of maturation parameters: example of cytochrome P450 3A4.

The aim of this work was to determine whether optimizing the study design in terms of ages and sampling times for a drug eliminated solely via cytochrome P450 3A4 (CYP3A4) would allow us to accurately estimate the pharmacokinetic parameters throughout the entire childhood timespan, while taking into account age- and weight-related changes. A linear monocompartmental model with first-order absorption was used successively with three different residual error models and previously published pharmacokinetic parameters ("true values"). The optimal ages were established by D-optimization using the CYP3A4 maturation function to create "optimized demographic databases." The post-dose times for each previously selected age were determined by D-optimization using the pharmacokinetic model to create "optimized sparse sampling databases." We simulated concentrations by applying the population pharmacokinetic model to the optimized sparse sampling databases to create optimized concentration databases. The latter were modeled to estimate population pharmacokinetic parameters. We then compared true and estimated parameter values. The established optimal design comprised four age ranges: 0.008 years old (i.e., around 3 days), 0.192 years old (i.e., around 2 months), 1.325 years old, and adults, with the same number of subjects per group and three or four samples per subject, in accordance with the error model. The population pharmacokinetic parameters that we estimated with this design were precise and unbiased (root mean square error [RMSE] and mean prediction error [MPE] less than 11% for clearance and distribution volume and less than 18% for k(a)), whereas the maturation parameters were unbiased but less precise (MPE < 6% and RMSE < 37%). Based on our results, taking growth and maturation into account a priori in a pediatric pharmacokinetic study is theoretically feasible. However, it requires that very early ages be included in studies, which may present an obstacle to the use of this approach. First-pass effects, alternative elimination routes, and combined elimination pathways should also be investigated.

Hypotension in Preterm Infants (HIP) randomised trial.

OBJECTIVE: To determine whether restricting the use of inotrope after diagnosis of low blood pressure (BP) in the first 72 hours of life affects survival without significant brain injury at 36 weeks of postmenstrual age (PMA) in infants born before 28 weeks of gestation. DESIGN: Double-blind, placebo-controlled randomised trial. Caregivers were masked to group assignment. SETTING: 10 sites across Europe and Canada. PARTICIPANTS: Infants born before 28 weeks of gestation were eligible if they had an invasive mean BP less than their gestational age that persisted for ≥15 min in the first 72 hours of life and a cerebral ultrasound free of significant (≥ grade 3) intraventricular haemorrhage. INTERVENTION: Participants were randomly assigned to saline bolus followed by either a dopamine infusion (standard management) or placebo (5% dextrose) infusion (restrictive management). PRIMARY OUTCOME: Survival to 36 weeks of PMA without severe brain injury. RESULTS: The trial terminated early due to significant enrolment issues (7.7% of planned recruitment). 58 infants were enrolled between February 2015 and September 2017. The two groups were well matched for baseline variables. In the standard group, 18/29 (62%) achieved the primary outcome compared with 20/29 (69%) in the restrictive group (p=0.58). Additional treatments for low BP were used less frequently in the standard arm (11/29 (38%) vs 19/29 (66%), p=0.038). CONCLUSION: Though this study lacked power, we did not detect major differences in clinical outcomes between standard or restrictive approach to treatment. These results will inform future studies in this area. TRIAL REGISTRATION NUMBER: NCT01482559, EudraCT 2010-023988-17.

Hospitalization for severe bacterial infections in children after exposure to NSAIDs: a prospective adverse drug reaction reporting study.

BACKGROUND: NSAIDs are widely used to treat fever and pain in children, but their possible role in the progression of some bacterial infections is controversial. OBJECTIVE: This study was performed to analyse reported cases of severe bacterial infection associated with NSAID exposure in children admitted for this reason to a general paediatric department. METHODS: This study was based on the reporting system of hospital admissions for severe bacterial infections in children after NSAID exposure, and followed the recommendations of the European Guidelines of Pharmacovigilance for medicines used in a paediatric population. Data were prospectively collected and reported by active daily surveillance in the department from November 2002 to November 2005. RESULTS: Thirty-two cases of severe bacterial infections (cellulitis, soft tissue abscesses, parapneumonic empyema, necrotizing pneumonia, adenophlegmon [fever and a tender, warm and easily compressible neck mass] and lateral or retropharyngeal abscesses) were identified in children who had received NSAIDs, principally ibuprofen, in an exposure window of 15 days before the beginning of the signs of infection. Staphylococcus aureus, group A streptococci and Streptococcus pneumoniae were identified. Seven (22%) children required surgical treatment, and four (13%) were hospitalized in an intensive care unit. CONCLUSIONS: The frequency of hospitalization for severe bacterial infection as a possible adverse effect of NSAID use was 0.6% (95% CI 0.4, 0.9) of all admissions during the study period. The frequency of severe bacterial infections after exposure to NSAIDs was elevated (one case per month) in the department studied. Further work is necessary to confirm these findings, given the potential for recruitment and protopathic biases in our study.

A population analysis of weight-related differences in lopinavir pharmacokinetics and possible consequences for protease inhibitor-naive and -experienced patients.

BACKGROUND: Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown. METHODS: A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations. RESULTS: A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg). CONCLUSIONS: These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients.

Population analysis of the pregnancy-related modifications in lopinavir pharmacokinetics and their possible consequences for dose adjustment.

OBJECTIVES: To investigate the possible necessity of an increase in lopinavir dose during pregnancy in order to achieve the concentrations previously defined as predictive of virological efficacy. PATIENTS AND METHODS: Lopinavir pharmacokinetics were investigated by a population approach performed on 145 HIV-infected women, including 74 pregnant women. The final model was used to determine the probability of achievement of the target trough concentrations by Monte Carlo simulations. RESULTS: The typical population estimates (inter-individual variability %) of apparent clearance (CL/F) and volume of distribution were 4.38 L/h (24%) and 58.4 L (59%), respectively. Pregnancy associated with a gestational age >15 weeks and delivery were found to increase lopinavir CL/F by 39% and 58%, respectively. With the standard 400 mg twice-a-day regimen, the probability of reaching the 1 mg/L target trough concentration for protease inhibitor (PI)-naive patients was 99% and 96% for non-pregnant and pregnant women, respectively. An important decrease in the probability of achieving the 5.7 mg/L target trough concentration for salvage therapy was observed for non-pregnant women (55%), this decrease being even greater for pregnant women (21%). Raising the lopinavir dose to 600 mg twice daily increased these probabilities to 87% and 53% for non-pregnant and pregnant women, respectively. CONCLUSIONS: Modification of the lopinavir dose is unlikely to be required for PI-naive pregnant women; however, in pregnant women who have previously received a PI, therapeutic drug monitoring and/or empirical increasing of the dose should be considered.

Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy.

PURPOSE: To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children. METHODS: LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration-time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults. RESULTS: LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6-20 mg/L target range for the trough concentration. DISCUSSION: Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.

Proposals for model-based paediatric medicinal development within the current European Union regulatory framework.

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop.We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.

Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease.

BACKGROUND: Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in many European countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (ARTIs) in children without chronic broncho-pulmonary disease. OBJECTIVES: The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for ARTIs in children without chronic broncho-pulmonary disease. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 4) which contains the Acute Respiratory Infections (ARI) Group's Specialized Register, MEDLINE (1966 to 2008), EMBASE (1980 to 2008); Micromedex (2008), Pascal (1987 to 2004), and Science Citation Index (1974 to 2008). SELECTION CRITERIA: To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo either alone or as an add-on therapy.To study safety, we also used trials comparing the use of acetylcysteine or carbocysteine versus active treatment or no treatment and case reports. DATA COLLECTION AND ANALYSIS: At least two review authors extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age. MAIN RESULTS: Six trials involving 497 participants were included to study efficacy. They showed some benefit from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because the data were unavailable. Thirty-four studies including the previous six trials involving 2064 children were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 48 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. AUTHORS' CONCLUSIONS: The results of this review have to be interpreted with caution because it was based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self-limiting diseases (for example, acute cough, bronchitis). Regarding children younger than two years, given concerns about safety, these drugs should only be used for ARTIs in the context of an RCT.

Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data.

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure-related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36-mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose-ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4-5.7 years) for the active S(+)-enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one-compartment model with zero-order absorption and first-order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36-mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms.

Facilitation of drug evaluation in children by population methods and modelling.

The pharmacokinetics and pharmacodynamics of drugs are different in adult and paediatric populations, the latter being particularly heterogeneous. These differences in pharmacokinetics and pharmacodynamics justify specific studies but raise a number of ethical and practical issues. The main practical difficulties to circumvent while performing clinical studies in children are the invasiveness of the procedures and the obstacles to patient recruitment. The invasiveness related to pain/anxiety and blood loss precludes the performance of classical pharmacokinetic studies in children in many instances, particularly in neonates and infants. Population approaches, which rely on pharmacokinetic-pharmacodynamic modelling, are particularly appealing in paediatric populations because these models can cope with sparse data. The relevance of population approaches to investigation of the dose-concentration-effect relationships and to qualitative/quantitative assessment of factors that may explain interindividual variability has already been emphasized. The aims of this review are to summarize the currently available literature on population pharmacokinetic-pharmacodynamic studies in children and to discuss a number of recent methodological developments that may facilitate the evaluation of drugs in this population by alleviating invasiveness and, subsequently, facilitating recruitment of patients. The present survey confirms that population approaches in paediatrics have already reached a large audience and that they are mostly used for analysis of sparse data. However, pharmacokinetic-pharmacodynamic studies in children are still scarce. New classes of models may extend the scope of the use of population models in paediatrics. Kinetic-pharmacodynamic models, where use of the term 'kinetic' rather than 'pharmacokinetic' emphasizes the absence of pharmacokinetic data, are indirect models where the (unobserved) drug kinetics are described by a single compartment involving a single rate constant. These models, which alleviate the need for blood samples used for the measurement of drug concentration, may be very useful in paediatric studies. Physiological and physiopathological models also have potential applications but require further development. Because the number of measurements in a single individual needs to be limited in children, it is crucial to optimize the design of the experiment in order to avoid inaccurate and unreliable results. In this review, formal optimization and simulation to evaluate a design are presented, and specific problems raised by the application of these techniques in paediatrics are addressed. Finally, the related technique of clinical trial simulation and its applications are presented and discussed.