Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

Abstract

What is already known about this subject• Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated.• We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis. What this study adds• Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability.• Descriptors of the relationship between age and clearance in premature neonates vary.• The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h − 1 70 kg − 1 (95% confidence interval 2.76, 4.98) from premature neonatal data. AimTo identify and quantify factors describing the variability of vancomycin clearance in premature neonates. MethodsPopulation pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24-34 weeks; postnatal age 11.9 days, range 1-27 days; weight 1.30 kg, range 0.42-2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data (604 observations). ResultsThe population estimate for volume of distribution ( V ) was 39 l 70 kg − 1 (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h − 1 70 kg − 1 at 24 weeks PMA to 2.02 l h − 1 70 kg − 1 by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, P MA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h − 1 70 kg − 1 (95% confidence interval 2.76, 4.98). ConclusionsSize, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.B. J. Anderson et al.

Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children

“…6, the clearance values of palivizumab in children are below those expected based on allometry alone. Studies by Anderson et al (2,3) show that changes in body weight alone do not adequately explain the changes in CL and volume of distribution in pediatric patients; maturational effects must also be considered as different organ/tissue/enzyme/transporter systems evolve and mature. Therefore, age and body weight were evaluated to characterize palivizumab PK in the infant population before covariate analysis.…”

Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children

“…The maturation of CL/F was described using a sigmoid E max model. This model was successfully applied previously to examine the maturation of vancomycin clearance in premature neonates (25). Compared with other models that have also been used to describe maturation (26,27,38,39), the sigmoid E max model has the distinct advantage of reaching an asymptotic mature value in older children or adults and not predicting biologically unreasonable values (22).…”

“…The maturation of CL/F in the patients was tested using a sigmoid maximum-effect (E max ) model to allow a gradual increase in clearance during early-life years and a mature clearance to be achieved at a later age, as follows (24,25)…”

Use of Modeling and Simulation in the Design and Conduct of Pediatric Clinical Trials and the Optimization of Individualized Dosing Regimens

“…This sigmoidal clearance maturation model has been used to describe vancomycin clearance in preterm and full‐term neonates 34, 35. For vancomycin, it was determined that 49% of the variability in clearance was explained by body weight, 18% by PMA, and 14% by renal function (as measured by serum creatinine concentration) 34.…”