Pediatric Patients With Solid or Hematological Tumor Disease: Vancomycin Population Pharmacokinetics and Dosage Optimization.

BACKGROUND: In pediatric cancer patients, determination of optimal vancomycin dosage is essential because of high risk of inadequate concentrations and bacterial resistance. The aim of this study was to determine vancomycin pharmacokinetic parameters in this population and propose dosage optimization to achieve optimal concentration. METHODS: We retrospectively reviewed the use of vancomycin in pediatric cancer patients with febrile neutropenia (hematological or solid tumor disease). Vancomycin was administered by continuous infusion, and dosages were adapted according to therapeutic drug monitoring results. Blood cultures were performed before the first dose of antibiotic. Vancomycin pharmacokinetic population parameters were determined using NONMEM software, and dosage simulations were performed according to the target concentration (20-25 mg/L). RESULTS: One hundred twenty-one patients were included in this study, representing 301 vancomycin concentrations. Blood cultures were positive in 37.5% of patients, and observed pathogens were mainly Staphylococcus spp. (43.8% methicillin resistant). Volume of distribution (95% confidence interval) was 34.7 L (17.3-48.0), and total apparent clearance (CL) (95% confidence interval) was correlated to body weight, tumor disease, and cyclosporine coadministration: CL = θCL × (WT/70) L/h with θCL = 3.49 (3.02-3.96), 4.66 (3.98-5.31), and 4.97 (4.42-5.41) in patients managed for hematological malignancies with or without cyclosporine coadministration and for solid malignancies, respectively. Based on simulation results, vancomycin dosage (milligram per kilogram) should be adapted to each child on the basis of its body weight and cyclosporine coadministration. CONCLUSIONS: Our results highlight the requirement to adapt vancomycin dosage in cancer pediatric population. Simulations have allowed to describe new dosage schedules, and a chart was created for clinicians to adapt vancomycin dosage.

Interaction of thiopental with esomeprazole in critically ill patients.

INTRODUCTION: Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug-drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental. METHOD: The study population comprised 52 critically ill patients (body weight 47.1-114 kg) aged 18-78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model. RESULT: A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (Vd) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively. CONCLUSION: Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug-drug interaction should be considered when a target concentration has to be reached.

Unintentional poisoning from decanted toxic household chemicals.

BACKGROUND: Although poisonings due to a toxic substance being decanted into a secondary container are often reported to poison centers, we were unable to locate prior European data about their circumstances, incidence and consequences. We sought to describe the circumstances and outcomes of this behavior. MATERIALS AND METHOD: We conducted a prospective study of all poison exposures involving transfer to a secondary container reported to our poison center during a six month interval (January 1, 2021 through June 30, 2021). We called patients and clinicians for follow up the next day. We used a prepared questionnaire and added the responses to the national database for French poison centers. RESULTS: We identified and included 238 patients (104 male, 134 female) with a median age of 39 years [range 0-94 y]. Exposure was mainly oral (n = 221), the secondary container was mainly a water bottle (n = 173), toxic substances were essentially cleaning products (n = 63) or bleach (n = 48). Symptoms were gastrointestinal (vomiting, diarrhea, abdominal pain) (n = 143) or respiratory (cough, dyspnea, aspiration pneumonia) (n = 15). The World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists Poisoning Severity Score was none in 76 cases (31.9%), minor in 147 (61.8%), moderate in 12 (5%), and severe in three cases (1.3%). Products that led to severe poisoning contained either ammonium hydroxide or sodium hydroxide. Two of the patients required intensive care treatment. At the end of the follow-up, 235 patients fully recovered, and three patients had sequelae. CONCLUSIONS: The study illustrates the risk of toxic substance transfer. Water bottles were the secondary containers in most exposures to decanted substances. Most had minor or no effects, but nearly one-quarter were admitted to the hospital. The few severe exposures involved either ammonium hydroxide or sodium hydroxide.

Deliberate Self-Poisoning with Plants in Southeastern France, a Poison Center 20-Year Report.

INTRODUCTION: In a few regions of the globe, deliberate botanical intoxication may induce significant rates of toxicity and fatality. The objective of this report was to describe plant self-intoxication using the experiences of the southeastern France poison control center (PCC) between 2002 and 2021. RESULTS: During those 20 years, 262 deliberate plants poisonings were reported involving 35 various plants. In most of the cases, poisoning was caused by Nerium oleander (n = 186, 71%), followed by the Datura genus (4.2%), Ricinus communis (3.8%), Taxus baccata (1.9%), Digitalis purpurea (1.2%), Aconitum nape (1.9%), Myristica fragans (1.5%), and Pyracantha coccine (1.2%). Through the 262 plants poisonings, 19 patients among the 186 Nerium oleander poisonings received Digifab as an antidote and 1 patient received physostigmine among the 11 Datura poisonings. Only four deaths were reported for this review, each involving Nerium oleander. DISCUSSION: The first involved species was Nerium oleander (71% of all plants poisonings), then Datura sp and Ricinus communis. It is explained by this native local species' important repartition. Most patients must be admitted to an emergency department for adapted medical care; however, only 41 of them described severe poisonings symptoms. Even fewer needed an antidote, only 20 patients. There is no protocol for the use of a specific treatment, and it might be interesting to develop one for this purpose. MATERIAL AND METHODS: This retrospective review was realized with files managed by the southeastern France PCC based in Marseille from 2002 to 2021. Our department covers the complete French Mediterranean coast, Corsica, and tropical islands (Reunion Island, Mayotte). For every patient, toxicity was evaluated using the Poison Severity Score (PSS).

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique des aminosides.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

[Level of evidence for therapeutic drug monitoring of aminoglycosides]. / Niveau de preuve du suivi thérapeutique pharmacologique des aminosides.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique de la teicoplanine.

Teicoplanin is a glycopeptid antibiotic used for treatment of serious infections caused by Gram+ bacteriae. The treatment scheme corresponds to an initial loading dose followed by maintenance dose. High interindividual pharmacokinetic variability and strong relation between high through concentrations, dose and clinical success, support the need of therapeutic drug monitoring using through concentrations. Achieving through concentrations ≥10-15 mg/L or ≥20-40 mg/L, regarding the measurement method and the infection severity, is recommended to increase clinical success rate. The level of proof of therapeutic drug monitoring is evaluated: "necessary".

[Level of evidence for therapeutic drug monitoring of teicoplatin]. / Niveau de preuve du suivi thérapeutique pharmacologique de la teicoplanine.

Teicoplanin is a glycopeptid antibiotic used for treatment of serious infections caused by Gram+ bacteriae. The treatment scheme corresponds to an initial loading dose followed by maintenance dose. High interindividual pharmacokinetic variability and strong relation between high through concentrations, dose and clinical success, support the need of therapeutic drug monitoring using through concentrations. Achieving through concentrations ≥ 10-15 mg/L or ≥ 20-40 mg/L, regarding the measurement method and the infection severity, is recommended to increase clinical success rate. The level of proof of therapeutic drug monitoring is evaluated: "necessary".

Buprenorphine exposures in adolescents and adults: a 10-year experience of a French Poison Control Center.

Buprenorphine has been used in pain and opioid addiction management for nearly 25 years. Compared to methadone, buprenorphine is thought to exhibit less side effects and respiratory depression in case of accidental or suicidal overdose. The aim was to describe the characteristics of exposures reported to a French Poison Control Center (PCC). We conducted a retrospective study including all buprenorphine exposures for which advice of our PCC was required between 2009 and 2018. After data extraction from the electronic medical files and anonymous transfer to an Access base, a statistical descriptive analysis was performed focusing on adolescents over 10 years old and adults. One hundred and ninety-nine cases were analyzed. The major circumstances of exposure were suicide attempts and overdoses in patients with previously identified substance abuse. Buprenorphine exposures have been reduced by 50% between 2009 and 2018. Coingestions, often with benzodiazepines or antidepressants, were almost systematic and 79% of all the series exhibited at least one symptom. Among the symptomatic cases, neurological effects were the most frequent (83%) and respiratory symptoms occurred in 13%. No deaths were registered. Severity did not exceed PSS1 in 80% of all the cases. Treatment was mainly symptomatic even though naloxone was required in at least 5% of the symptomatic cases. Within 24 h after exposure, 120 patients were discharged from the emergency department. Despite loss to follow-up, our results suggest that buprenorphine is relatively safe.

Buprenorphine poisoning in children: a 10-year-experience of Marseille Poison Center.

Buprenorphine is a µ-partial agonist and k-antagonist acting on central opioid receptors. Patented for analgesia in 1968, buprenorphine has been used as opioid substitutive therapy since the 1990s, as well as methadone. The aim was to document pediatric poisoning, to discover the severity, and to evaluate the treatment with naloxone. All pediatric poisonings reported to the poison control center Marseille (France)-from January 1, 2009 to December 31, 2018-were included. Analysis put value on gender, age, estimated quantity, symptoms and their delay, place of treatment, medical treatment, utilization of antidotes, severity of intoxications, and patients' outcome. Fifty-four infant poisonings with buprenorphine were recorded, doses varied between 1 and 36 mg, and children showed mainly neurological (somnolence, miosis…) and gastroenteric (vomiting) effects. Pulmonary effects were described for four children. According to the poisoning severity score, 8 intoxications were classified as 'no symptoms or signs', 37 as minor poisonings, 3 as moderate, none as severe or fatal and 6 were unknown. Medical care was required for 46 children, and four of them were treated with naloxone. Buprenorphine poisoning can cause neurological, gastroenteric, and respiratory symptoms. Even licking a tablet leads to intoxication because of maximal tablet's absorption while placing it under the tongue. Hospital admission is necessary even at small doses. Naloxone was efficient in the four described cases. Parents have to be aware of the poisoning risk with buprenorphine. Recently, commercialized instantly dissolving formulations could cause more severe intoxications.

Biological rhythms: a neglected factor of variability in pharmacokinetic studies.

Biological rhythms may influence drug response (chronopharmacology) and some chronopharmacological studies have underlined the influence of time of day on drug pharmacodynamics and pharmacokinetics. The aim of the present review is to underline how biological rhythms may interfere with drug kinetics and to try to underline when, how, and why taking into account the moment of administration of a drug. Many physiological factors, possibly implicated in different steps of the fate of drugs in the organism (e.g., absorption, distribution, metabolism, and elimination) vary along the 24 h scale. Taking into account biological rhythms in kinetic studies, should be indicated when the concerned drug will be used in a chronobiological disease (e.g., asthma, cancer, depression, hypertension, gastrointestinal diseases, rheumatisms), etc. In case of a drug characterised by a high inter- and intra-variability, a narrow therapeutic range or when the drug will be further used following a once-a-day formulation. It is of importance to rigorously control factors which are known to influence pharmacokinetic processes in chronokinetic studies. Time of day has to be regarded as an additional variable to influence the kinetics of a drug.

Nebulisers comparison with inhaled tobramycin in young children with cystic fibrosis.

BACKGROUND: This randomised cross-over pilot study was undertaken in 10 cystic fibrosis children aged 10 to 63 months to describe lung absorption of tobramycin delivered by the PariLC+/PariTurboboyN (Pari GmbH) and the disposable NL9M/AtomisorBoxPlus (Diffusion Technique Française) nebulising systems. METHODS: Each child inhaled 300 mg tobramycin delivered with one or the other apparatus via a facemask in two separate and standardised sessions. Urine was collected for 6 h. Tobramycin concentrations determined by immunoprecipitation were expressed in mg per g of creatinine and compared by a Wilcoxon test for matched pairs. The influences of age, weight and Brasfield score on this parameter were evaluated by correlation tests, and those of sex, previous nebulisation treatment, and crying or coughing were evaluated by Student's t-test. RESULTS: The amount of tobramycin measured in urines was low and variable. Median values for urinary tobramycin concentration were 47.6 mg/g (14.9-79.6) with the PariLC+ and 42.6 mg/g (6.3-112.8) with the NL9M (p=0.6). PariLC+ delivered tobramycin in 22 min and NL9M in 12 min (p=0.005). Crying or coughing dramatically reduced the amount of tobramycin collected. CONCLUSION: This pilot study shows that evaluation of nebulisers based on tobramycin renal excretion is feasible in young children with cystic fibrosis.

Chronopharmacokinetics of imipenem in the rat.

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C(max), T(max), elimination half-life (t(1/2)), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C(max) (49%), T(max) (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.

Regulation of Neuroinflammation: What Role for the Tumor Necrosis Factor-Like Weak Inducer of Apoptosis/Fn14 Pathway?

Observed in many central nervous system diseases, neuroinflammation (NI) proceeds from peripheral immune cell infiltration into the parenchyma, from cytokine secretion and from oxidative stress. Astrocytes and microglia also get activated and proliferate. NI manifestations and consequences depend on its context and on the acute or chronic aspect of the disease. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway has been involved in chronic human inflammatory pathologies such as neurodegenerative, autoimmune, or malignant diseases. New data now describe its regulatory effects in tissues or fluids from patients with neurological diseases. In this mini-review, we aim to highlight the role of TWEAK/Fn14 in modulating NI in multiple sclerosis, neuropsychiatric systemic lupus erythematosus, stroke, or glioma. TWEAK/Fn14 can modulate NI by activating canonical and non-canonical nuclear factor-κB pathways but also by stimulating mitogen-activated protein kinase signaling. These downstream activations are associated with (i) inflammatory cytokine, chemokine and adhesion molecule expression or release, involved in NI propagation, (ii) matrix-metalloproteinase 9 secretion, implicated in blood-brain barrier disruption and tissue remodeling, (iii) astrogliosis and microgliosis, and (iv) migration of tumor cells in glioma. In addition, we report several animal and human studies pointing to TWEAK as an attractive therapeutic target.

Nicotine and metabolites determination in human plasma by ultra performance liquid chromatography-tandem mass spectrometry: a simple approach for solving contamination problem and clinical application.

A quantitative method using ultra performance liquid chromatography-tandem mass spectrometry is described for simultaneous determination of nicotine and its metabolites (cotinine and trans-3'- hydroxycotinine) in human plasma. Aliquots of 0.25 mL of plasma specimens were used for analysis, and 3 analytes were extracted by liquid-liquid extraction. The main problem was blank plasma contamination with environmental nicotine. Activated charcoal was used to avoid this analytical interference. For optimized chromatographic performance, a basic mobile phase consisting of 0.2% ammonia in water (mobile phase A, pH10.6) and acetonitrile (mobile phase B) was selected. The analytes were separated on a 50 mm × 2.1 mm BEH C18 column, 1.7 µm particle size, and quantified by MS/MS using multiple-reaction monitoring (MRM) in positive mode. The chromatographic separation was achieved in 3 min followed by 1.2 min of column equilibration. The calibration curves were linear in the concentration range of 10-1000 ng/mL with correlation coefficients exceeding 0.99. Within-day precisions and between-day precisions (CV, %) were <15 %. The accuracy expressed as bias was within ±15% for all analytes. The recovery values ranged from 50% to 97%. The ions used for quantification of nicotine, cotinine and 3-OH-cotinine were 166.9 > 129.7; 176.9 > 79.7; 192.9 > 79.7 m/z, respectively. The original blank sample preparation solved the problem of contamination in a cost-effective and efficient way. The validated method has been routinely used for analysis of nicotine and metabolites and determination of hydroxycotinine/cotinine metabolic ratio. This biomarker seems to be interesting at predicting response of nicotine patch replacement therapies.

Circadian rhythms of oxidative phosphorylation: effects of rotenone and melatonin on isolated rat brain mitochondria.

Mitochondrial experiments are of increasing interest in different fields of research. Inhibition of mitochondrian activities seems to play a role in Parkinson's disease and in this regard several animal models have used inhibitors of mitochondrial respiration such as rotenone or MPTP. Most of these experiments were done during the daytime. However, there is no reason for mitochondrial respiration to be constant during the 24 h. This study investigated the circadian variation of oxidative phosphorylation in isolated rat brain mitochondria and the administration-time-dependent effect of rotenone and melatonin. The respiratory control ratio, state 3 and state 4, displayed a circadian fluctuation. The highest respiratory control ratio value (3.01) occurred at 04:00 h, and the lowest value (2.63) at 08:00 h. The highest value of state 3 and state 4 oxidative respiration occurred at 12:00 h and the lowest one at 20:00 h. The 24 h mean decrease in the respiratory control ratio following incubation with melatonin and rotenone was 7 and 32%, respectively; however, the exact amount of the inhibition exerted by these agents varied according to the time of the mitochondria isolation. Our results show the time of mitochondrial isolation could lead to interindividual variability. When studies require mitochondrial isolation from several animals, the time between animal experiments has to be minimized. In oxidative phosphorylation studies, the time of mitochondria isolation must be taken into account, or at least specified in the methods section.

[Involvement of a public pharmacology laboratory in pharmacokinetic studies]. / Rôle d'un laboratoire hospitalier de pharmacologie dans les études pharmacocinétiques.

Pharmacokinetic studies can be performed before or after a drug is marketed. Indeed, extensive use of a new drug can uncover situations that it has not been possible to investigate before market application. Hospital departments of pharmacology are often involved in these complementary studies. They can design the study, initiate it in a clinical investigation centre, measure plasma concentrations, analyse the pharmacokinetic data, and write the report. If the extent of the scientific involvement of public pharmacology laboratories is strictly demarcated, financial support for nonsponsored studies by the pharmaceutical industry is problematical. Indeed, it is difficult to obtain funds to study the concentration-toxicity relationship or a drug-drug interaction for a compound for which the patent has expired. In addition, such studies have an excess cost, mainly because of the expense associated with drug measurements. Also, the medical time devoted to research is not rewarded by institutions. This situation will become more complicated because of the restrictive legislative framework imposed by the European directive.

Population pharmacokinetics of ertapenem in juvenile and old rats.

Ertapenem is a parenteral broad-spectrum carbapenem active against Gram-negative pathogens, which has been approved for treatment of different infectious situations in adults and children. Favourable pharmacokinetics and pharmacodynamics have been established in young adults. In the elderly, dosing regimen adaptations are not recommended. Nevertheless, pharmacokinetic studies in paediatrics have not been published yet. The aim of this study was to document whether age influenced ertapenem disposition by comparing its pharmacokinetics in three groups of rats. Rats were separated into three groups: very young rats 21-day-old, 10-week-old and 7-month-old rats. A population pharmacokinetic model was built and evaluated, using the NONMEM software. Pharmacokinetic parameters, interindividual variability and residual variability were estimated. The final model was evaluated by a bootstrap procedure and visual predictive check. The ertapenem concentration-time data were best described by a one-compartment model with zero-order input and first-order elimination. Effect of very young and old ages was estimated on central volume and clearance. Model evaluation indicated that the model was robust and parameter estimates were accurate. Central volume was found to be dependent on age and increase with age. Although the dosing regimen was weight adjusted, clearance was found to depend not only on age but also on weight. This study clearly documents changes in ertapenem pharmacokinetics according to group of age. These results suggest that paediatric dosing regimen cannot be directly extrapolated from a pharmacokinetic model in young adults unless it took into account age-induced modifications.

Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.

Vancomycin: Predictive Performance of a Population Pharmacokinetic Model and Optimal Dose in Neonates and Young Infants.

INTRODUCTION: Model evaluation is an important issue in population pharmacokinetic analyses. The objectives were to evaluate the predictive performance of previously published pediatric population pharmacokinetic models for vancomycin in a new data set and to propose an optimal dose to obtain a vancomycin concentration target. METHODS: External evaluation was conducted for all the published models of vancomycin in neonates and young infants with a new data set of 70 patients. Bias and accuracy were calculated. Advanced analyses were performed to evaluate the predictive performance of the best model. This population pharmacokinetic analysis was performed to simulate doses of vancomycin according to the appropriate target concentration. RESULTS: All models gave almost the same results, except 2 that were not acceptable. Nevertheless, the model described by Oudin et al presented the best results with a bias and accuracy of 4.0% and 27.8%, respectively. Simulations showed that the maintenance dose should be adjusted more precisely to each neonate based on his or her weight and serum creatinine value. CONCLUSION: Simulations have allowed the authors to describe new dosage schedules, and a chart was created to help clinicians to adapt dosage of vancomycin. Because of pharmacokinetic variability, vancomycin still requires therapeutic drug monitoring.