Linked ArticlesThis article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685–7. doi: 10.1111/bcp.13230 AimWhen different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model‐based meta‐analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function).MethodsA systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation.ResultsNo model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), –4.1 (5), –9.2 (4), –10.8 (5) and –10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped.ConclusionNo evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.
Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies. Key PointsPharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children, and the so-called 'population' approach is suitable for rich or sparse data in terms of the number of samples per subjectThe utility of pediatric PK models can be increased by using a standardized approach to scaling: a suggested method for scaling clearance (CL) is a combination of allometric weight scaling with a sigmoid function to account for organ maturation. This should be used a priori, as a 'base' approach, allowing the effects of age and size to be delineated from other patient-specific factors, such as disease state and organ (dys)function When determining the pediatric dose, instead of directly scaling the dose from adults to children, the pediatric PK parameter estimates should be obtained from a PK model with a standardized scaling approach in order to avoid the use of arbitrary cut-off values (of age/weight) according to a specific (nonstandardized) CL-scaling formula Significant progress has recently been made on pediatric PK modeling; a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects PKPD model-based dose individualization is becoming increasingly popular as the age of personalized medicine dawns
T he aminoglycoside antibiotic gentamicin is the most commonly used antimicrobial in neonatal units (1, 2) and is effective against Gram-negative bacteria. Gentamicin use is limited by its narrow therapeutic index and risk of toxicity, specifically, nephro-and ototoxicity (3). It is not metabolized in the liver (4) and is almost entirely eliminated by the kidneys; clearance therefore depends on renal function. During the first 2 weeks of life, renal and intrarenal blood flow increase rapidly, causing a steep rise in the glomerular filtration rate (GFR) (5, 6).Therapeutic drug monitoring (TDM) is required to ensure maximal efficacy and, in particular, minimal toxicity, particularly in the neonatal population, where the variability in pharmacokinetic (PK) parameters is large. Dose individualization approaches focus on toxicity (7, 8) and include single-level methods and nomograms (9, 10), area under the curve (AUC) methods (11), and Bayesian methods (12). The use of nomograms is limited as they cannot readily incorporate covariates affecting PK parameters. AUC methods use a simplified 1-compartment PK model and require at least two gentamicin measurements, which is not appropriate in neonates with limited blood volumes. These drawbacks make Bayesian approaches the most attractive for newborn infants.Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13-24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period. Although gentamicin is not a new drug, its dosing and monitoring are still current issues as identified in the United Kingdom National Patient Safety alert (http://www.nrls .npsa.nhs.uk/alerts/?entryid45ϭ66271) and in a recent publication by Valitalo et al. (27), who used simulations to define dosing guidelines.We aimed to investigate whether opportunistic sampling can predict trough gentamicin concentrations so that standard TDM can be performed using a blood sample taken for other purposes Citation Germovsek E, Kent A, Metsvaht T, Lutsar I, Klein N, Turner MA, Sharland M, Nielsen EI, Heath PT, Standing JF, the neoGent Collaboration. 2016. Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.
BackgroundSepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.ObjectivesTo determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).MethodsData were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.ResultsA one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.ConclusionsSimulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.
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