Drug disposition and clinical practice in neonates: Cross talk between developmental physiology and pharmacology

Smits, Anne; Annaert, Pieter; Allegaert, Karel

doi:10.1016/j.ijpharm.2012.03.035

Cited by 42 publications

(57 citation statements)

References 37 publications

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“…An appropriate neonatal dosage regimen needs to integrate the rapid developmental changes during the neonatal period, as reflected by covariates influencing drug disposition (13). As vancomycin is almost entirely eliminated by the kidneys, covariates reflecting both renal maturation and renal function should be taken into account to personalize the vancomycin dosage.…”

Section: Discussionmentioning

confidence: 99%

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

Leroux

Jacqz-Aigrain

Biran

et al. 2016

Antimicrob Agents Chemother

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N eonatal bacterial sepsis, exacerbated by neonatal immunodeficiency (1), remains a major cause of mortality and morbidity in newborns (2). Vancomycin is widely used for the treatment of late-onset sepsis caused by methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci in neonatal intensive care units (NICUs) (3); however, the clinical use of vancomycin is still hampered by its narrow therapeutic index and high pharmacokinetic variability (4). Indeed, de Hoog et al. reported that vancomycin clearance and half-life varied between 0.63 and 1.4 ml/ kg/min and between 3.5 and 10 h in neonates, respectively (4). The common adverse effects of vancomycin are nephrotoxicity and ototoxicity; however, it has been shown that neonates tolerated vancomycin better than adults. Safety data for a high dosing regimen and long-term follow-up are still lacking.The pharmacokinetic modeling approach is often applied to evaluate and optimize antimicrobial therapy in neonates (5). To date, vancomycin is one of the best-studied antimicrobials, and numerous studies have been conducted to characterize its pharmacokinetic parameters and to identify individual factors influencing variability (6). However, the clinical application of modelbased personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a patient-tailored dose of vancomycin in neonates. Model-based patient-tailored dose of vancomycin. Special training was conducted in each NICU. We first informed the staff of the clinical pharmacology of vancomycin, its pharmacokinetic variability, and a large variation of dosage schedules currently used. We then explained the principles of individual dosage adaptation and how we developed the Excel dosing calculator using the results from our published population pharmacokinetic model (6). MATERIALS AND METHODS Neonates receiving vancomycin as a continuous infusion in one of threeIn order to calculate the patient-tailored dosing of vancomycin for each neonate, neonatologists had to enter four patient covariates in the calculator, including birth weight (in grams), current weight (in grams), postnatal age (PNA; in days), and serum creatinine concentration (in micromoles per liter) measured within 48 h of starting vancomycin treatment. The developed calculator was locked, and no other information was required. The patient-tailored dose is calculated automatically by using the following pharmacokinetic equations.Maintenance dose ϭ Target concentration ϫ CL ϫ 24 hwhere the loading dose is in milligrams, the maintenance dose is in milligrams per 24 h, the target concentration is in milligrams per liter, V (vol-

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Section: Discussionmentioning

confidence: 99%

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

Leroux

Jacqz-Aigrain

Biran

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…To determine such ratio, MIC is based on sensitivity and resistance breakpoints of microorganisms provided by ‘The European Committee on Antimicrobial Susceptibility Testing—EUCAST‘ or by the ‘Clinical Laboratory Standards Institute’11–13 while AUC is patient dependant. Therefore, appropriate neonatal dosing needs to integrate the rapid developmental changes of the neonatal period, as reflected by covariates influencing drug disposition 14. Depending on the drug, these covariates are markers of size and maturation and may include gestational, postnatal, postmenstrual age, creatine concentration liver function tests and so on.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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International audienceOBJECTIVE: 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

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“…Renal clearance of drugs increases with increasing gestational age, postnatal age, and body weight (7, 18). Mechanisms of renal excretion affected by these factors are glomerular filtration (GFR), active tubular secretion, and tubular reabsorption.…”

Section: Unique Physiology In Neonatesmentioning

confidence: 99%

Dosing in neonates: special considerations in physiology and trial design

Smith

2014

Pediatr Res

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Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that makes extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.

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Drug disposition and clinical practice in neonates: Cross talk between developmental physiology and pharmacology

Cited by 42 publications

References 37 publications

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

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

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

Dosing in neonates: special considerations in physiology and trial design

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