Pharmacokinetic model for vancomycin performed with sparse data on neonates
Pascal Chanu (1), Audrey Janoly-Dumenil (2), Nathalie Bleyzac (2), Jacques Bourgeois (3), Brigitte Tranchand (1)
(1) Centre Léon Bérard; (2) Pharmacy-Hôpital Debrousse; (3) Neonatalogy unit-Hôpital Debrousse
Objectives: The marked inter- and intra patient variability of the pharmacokinetics of numerous antibiotics is well known, especially in neonates. Moreover, we can presuppose that there is, at some extent, some degree of variability in effect during vancomycin therapy and that this variability is in some fashion related to plasma levels and to the administered dose of drug. In the present study, we tried to perform modelling of vancomycin, by using covariates on a large cohort in order to reduce inter- and intra patient variability. Indeed, it would be useful to predict pharmacokinetic parameters, clearance (Cl) and volume of distribution (Vd) of central compartment, in order to individualize dosage regimen with minimal disturbance to the neonates.
Patients and Methods: Sparse data from 145 courses of vancomycin upon neonates up to one month old were recorded. Each treatment consisted in either a continuous 24 hour infusion (96 patients) or in a 2 hour infusion of vancomycin three times per day (49 patients). The mean number of samples per patient was 1.8 and ranged from 1 to 5 samples. Vancomycin was assayed by an immuno - enzymatic method (EMIT). Covariates collected were body weight (Bw) (range [0.52 ; 5] kg), post conceptional age (Apc) (range [26.4 ; 55.3] weeks), sex (M=1, W=2, ratio M/F = 1.13), creatinin clearance (ClCr) (range : [4.3 ; 59.3] ml.min-1/1.73 m²) and height (range : [29.5 ; 60] cm). Data analysis was performed using NONMEM version 5 under Visual-NM.
Results: The best model for vancomycin was a two-compartment model associated to an additive error model (ADVAN 3 TRANS 4). The significant covariates were Apc and Bw for clearance and Bw for volume of distribution. The objective function decreased from 1474 to 1238 after inclusion of these covariates and variability in clearance decreased from 86% to 43%.
Conclusion: Such a population model could allow physicians to predict pharmacokinetic parameters (Cl and Vd) and thus to prescribe a priori amounts of vancomycin for neonates with more safety and more efficiency.