Despite nearly five decades of clinical use, vancomycin has retained a significant and uncontested niche in the antibacterial arsenal because of its consistent activity against almost all Gram-positive bacteria. Nevertheless, major vancomycin toxicities have been reported in the literature - in particular, nephrotoxicity and ototoxicity. Vancomycin pharmacokinetics have been described in numerous studies for 25 years. This review presents a synthesis of the reported population pharmacokinetic models of vancomycin. The objective was to determine if there was a consensus on a structural model and which covariates were identified. A literature search was conducted from the PubMed database, from its inception through December 2010, using the following terms: 'vancomycin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated. Twenty-five articles were included in this review: 15 models concerned paediatric patients and ten models were conducted in adults. In neonates and infants, the pharmacokinetics of vancomycin were mainly described by a one-compartment model, whereas in adults, a two-compartment model was preferentially used. Various covariates were tested but only three (age, creatinine clearance [CL(CR)] and body weight) were included in almost all of the described models. After inclusion of these covariates, the mean (range) values of the interindividual variability in the clearance and volume of distribution were 30% (15.6-45%) and 23% (12.6-48%), respectively. The mean (range) value of the residual variability was 20% (7-39.6%). This review highlights the numerous population pharmacokinetic models of vancomycin developed in recent decades and concludes with relevant information for clinicians and researchers. To optimize vancomycin dosage, this review points out the relevant covariates according to the target population. In adults, dosage optimization depends on CL(CR) and body weight, while in children, it depends on age, body weight and CL(CR). For future population pharmacokinetic studies, a sensitive liquid chromatography-tandem mass spectrometry method could be used and new covariates such as cardiac output or possible renal transporters could be tested. Finally, we suggest that external evaluation should be the first step in a pharmacokinetic analysis of vancomycin rather than describing a new model.

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Three decades after its introduction, pharmacokinetic population approaches have become a reference method for drug modelling, particularly in paediatrics. The main practical limitation in this specific population is the collected blood volume. Pharmacokinetic population approaches using sparse sampling may resolve this issue. The pharmacokinetics of many drugs have been studied during the last 25 years using such methods. This review summarizes all of the published studies concerning population pharmacokinetic approaches in paediatric subjects from neonate to 2 years old. A literature search was conducted using the PubMed database, from 1985 to December 2010, using the following terms: pharmacokinetic(s), population, paediatric/pediatric and neonate(s). Articles were excluded if they were not pertinent according to our criteria. References of all relevant articles were also evaluated. Ninety-eight studies were included in this review. The following information was extracted from the articles: drug name, therapeutic class, population size, age of patients, number of samples per patient, covariates used for clearance and volume of distribution estimates, software used for modelling and validation methods. An increasing rate of publications over the years was observed; 44 different drugs were studied using a pharmacokinetic population approach. Antibacterials were the most studied class of drugs, including a large number of studies devoted to vancomycin and gentamicin. It must be underlined that few studies have been performed on anticonvulsant drugs and anaesthetics used in clinical daily practice conditions.

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.