Stéphanie Leroux

Therapeutic guidelines for prescribing antibiotics in neonates should be evidence-based: a French national survey

Objective This survey aims to describe and analyse the dosage regimens of antibiotics in French neonatal intensive care units (NICUs). Methods Senior doctors from 56 French NICUs were contacted by telephone and/or email to provide their local guidelines for antibiotic therapy. Results 44 (79%) NICUs agreed to participate in this survey. In total, 444 dosage regimens were identified in French NICUs for 41 antibiotics. The number of different dosage regimens varied from 1 to 32 per drug (mean 9, SD 7.8). 37% of intravenous dosage regimens used a unique mg/kg dose from preterm to full-term neonates. Doses and/or dosing intervals varied significantly for 12 antibiotics (amikacin, gentamicin, netilmicin, tobramycin, vancomycin administered as continuous infusion, ceftazidime, cloxacillin, oxacillin, penicillin G, imipenem/cilastatin, clindamycin and metronidazole). Among these antibiotics, 6 were used in more than 70% of local guidelines and had significant variations in (1) maintenance daily doses for amikacin, imipenem/cilastatin, ceftazidime and metronidazole; (2) loading doses for continuous infusion of vancomycin; and (3) dosing intervals for gentamicin and amikacin. Conclusions A considerable inter-centre variability of dosage regimens of antibiotics exists in French NICUs. Developmental pharmacokinetic–pharmacodynamic studies are essential for the evaluation of antibiotics in order to establish evidence-based dosage regimens for effective and safe administration in neonates.

How to use vancomycin optimally in neonates: remaining questions

In neonates, vancomycin, a narrow-spectrum antibiotic, is the first choice of treatment of late-onset sepsis predominantly caused by Gram-positive bacteria (coagulase-negative staphylococci and enterococci). Although it has been used for >50 years, prescribing the right dose and dosing regimen remains a challenge in neonatal intensive care units for many reasons including high pharmacokinetic variability, increase in the minimal inhibition concentration against staphylococci, lack of consensus on dosing regimen and way of administration (continuous or intermittent), duration of treatment, use of therapeutic drug monitoring, limited data on short- and long-term toxicity, risk of mutant selection and errors of administration linked to concentrated formulations. This article highlights and discusses future research directions, with specific attention given to dosing optimization of vancomycin, including the advantages of modeling and simulation approaches.

Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

ABSTRACT Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.

Dosage individualization in children: integration of pharmacometrics in clinical practice

BackgroundChildren 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 sourcesBased 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.ResultsAntibiotics 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.ConclusionThe 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.

A Delphi process to optimize quality and performance of drug evaluation in neonates.

Background Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. The objective of this work was to identify the major criteria considered necessary for selecting neonatal intensive care units that are able to perform drug evaluations competently. Methodology and Main Findings This Delphi process was conducted with an international multidisciplinary panel of 25 experts from 13 countries, selected to be part of two committees (a scientific committee and an expert committee), in order to validate criteria required to perform drug evaluation in neonates. Eighty six items were initially selected and classified under 7 headings: “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6). Sixty-one items were retained and headings were rearranged after the first round, 34 were selected after the second round. A third round was required to validate 13 additional items. The final set includes 47 items divided under 5 headings. Conclusion A set of 47 relevant criteria will help to NICUs that want to implement, conduct or participate in drug trials within a neonatal network identify important issues to be aware of. Summary Points 1) Neonatal trials remain difficult to conduct for several reasons: in particular the need for study sites to have an existing infrastructure in place, with trained investigators and validated quality procedures to ensure good clinical, laboratory practices and a respect for high ethical standards. 2) The present Delphi study was conducted with an international multidisciplinary panel of 25 experts from 13 countries and aims to identify the major criteria considered necessary for selecting neonatal intensive care units (NICUs) that are able to perform drug evaluations competently. 3) Of the 86 items initially selected and classified under 7 headings - “NICUs description - Level of care” (21), “Ability to perform drug trials: NICU organization and processes (15), “Research Experience” (12), “Scientific competencies and area of expertise” (8), “Quality Management” (16), “Training and educational capacity” (8) and “Public involvement” (6) - 47 items were selected following a three rounds Delphi process. 4) The present consensus will help NICUs to implement, conduct or participate in drug trials within a neonatal network.

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

ABSTRACT Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.

Drug versus placebo randomized controlled trials in neonates: A review of ClinicalTrials.gov registry

Background Despite specific initiatives and identified needs, most neonatal drugs are still used off-label, with variable dosage administrations and schedules. In high risk preterm and term neonates, drug evaluation is challenging and randomized controlled trials (RCT) are difficult to conduct and even more is the use of a placebo, required in the absence of a reference validated drug to be used as comparator. Methods We analyzed the complete ClinicalTrials.gov registry 1) to describe neonatal RCT involving a placebo, 2) to report on the medical context and ethical aspects of placebo use. Results Placebo versus drug RCT (n = 146), either prevention trials (n = 57, 39%) or therapeutic interventions (n = 89, 61%), represent more than a third of neonatal trials registered in the National Institute of Health clinical trial database (USA) since 1999. They mainly concerned preterm infants, evaluating complications of prematurity. Most trials were conducted in the USA, were single centered, and funded by non-profit organizations. For the three top drug trials evaluating steroids (n = 13, 9.6%), erythropoietin (EPO, n = 10, 6.8%) and nitric oxide (NO, n = 9, 6.2%), the objectives of the trial and follow-up were analyzed in more details. Conclusion Although a matter of debate, the use of placebo should be promoted in neonates to evaluate a potential new treatment, in the absence of reference drug. Analysis of the trials evaluating steroids showed that long-term follow-up of exposed patients, although required by international guidelines, is frequently missing and should be planned to collect additional information and optimize drug evaluation in these high-risk patients.

Developmental pharmacogenetics of CYP2C19 in neonates and young infants: omeprazole as a probe drug

AIMS Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. METHODS Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic-pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM. RESULTS Data fitted a one-compartment parent and metabolite model with first-order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5-hydroxy-omeprazole (CLOMZ-M1 ) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model-predicted CLOMZ-M1 are 12.5% (5-95% percentile: 3-14.9%) and 44.9% (5-95% percentile: 29.9-72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model-predicted absorption rate constant of omeprazole is 6.93 (5-95% percentile: 3.01-14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5-95% percentile: 0.86-3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild-type patients. CONCLUSIONS Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation.

Drug evaluation in children 10 years after the European pediatric regulation current challenges and perspectives

The European pediatric regulation, that entered into force in June 2007 with the objectives to improve the health of children in Europe, dramatically changed the regulatory environment of paediatric drug evaluation in Europe. The recent 10years European medicines agency (EMA) report showed that the number of paediatric trials increased and that 238 new medicines and indications for use in children were authorised in the EU. However, results remain constrated and futur developments require european collaborations beween all experts in developmental pharmacology, drug evaluation and trial conduct, training, all aspects already considered in different EU paediatric programs.

Principles and applications of pharmacometrics in drug evaluation in children

Drug evaluation in children is difficult for many well-identified reasons and many drugs are still used off-label. Innovative approaches are particularly adapted to the paediatric and neonatal populations, as clinical trials are difficult to conduct, need adapted designs in order to define the optimal dosage regimen in many diseases and therapeutic areas. Population approaches to define pharmacokinetics and pharmacokinetic/pharmacodynamics are now more currently used to define dosing regimens, adapted to the different paediatric and neonatal age groups, that allow to increase efficacy and reduce toxicity, by taking into account factors explaining variability in drug response. Such approaches are presented and the evaluation of vancomycin in neonates is detailed as different steps allowed validation of the optimal strategy to administer vancomycin in neonates.