the central compartment (mg/h). There is clearance (Cl) from the central compartment measured in L/h, which has Volume (V) measured in liters (L). The central and peripheral compartments are connected by the first-order rate constants Kcp and Kpc (h-1). Once the standard model was developed, the potential effect of growth (size) and development (maturity) on the PK of teicoplanin was investigated. This was conducted using clinical measures that are readily accesible, such as weight and age. We also examined the relationships between other potentially relevant covariates and the PK (e.g. albumin). The Bayesian individual posterior median estimates for clearance and volume of distribution were obtained from the standard model for each patient. These were then plotted against the covariates of interest to interrogate any possible relationships. In neonates and children, clearance generally scales with size in a nonlinear manner that is best described using a power function. A scaling exponent of 0.75 is most frequently used (i.e. Clearance is proportional to weight0.75). In addition, physiological maturation may also affect clearance and this is especially important for neonates and young infants (18, 19). In our model building process, we switched from clearance to using Ke (h-1) as the first-order elimination rate constant, where Ke = Cl/V and Ke is proportional to weight-0.25. While it is possible to directly estimate the scaling exponents, we chose to fix these values as previously described by us and others (18–20). There is a theoretical basis for using fixed scaling exponents that is related to fundamental relationships between size and a range of biological functions. Weight for each individual patient was normalized to a 70 kg adult (19, 21). Consequently, values for Ke0 and V0 approximate adult values.
the central compartment (mg/h). There is clearance (Cl) from the central compartment measured in L/h, which has Volume (V) measured in liters (L). The central and peripheral compartments are connected by the first-order rate constants Kcp and Kpc (h-1). Once the standard model was developed, the potential effect of growth (size) and development (maturity) on the PK of teicoplanin was investigated. This was conducted using clinical measures that are readily accesible, such as weight and age. We also examined the relationships between other potentially relevant covariates and the PK (e.g. albumin). The Bayesian individual posterior median estimates for clearance and volume of distribution were obtained from the standard model for each patient. These were then plotted against the covariates of interest to interrogate any possible relationships. In neonates and children, clearance generally scales with size in a nonlinear manner that is best described using a power function. A scaling exponent of 0.75 is most frequently used (i.e. Clearance is proportional to weight0.75). In addition, physiological maturation may also affect clearance and this is especially important for neonates and young infants (18, 19). In our model building process, we switched from clearance to using Ke (h-1) as the first-order elimination rate constant, where Ke = Cl/V and Ke is proportional to weight-0.25. While it is possible to directly estimate the scaling exponents, we chose to fix these values as previously described by us and others (18–20). There is a theoretical basis for using fixed scaling exponents that is related to fundamental relationships between size and a range of biological functions. Weight for each individual patient was normalized to a 70 kg adult (19, 21). Consequently, values for Ke0 and V0 approximate adult values.
AAC_00707-17_Individualized%20Therapy%20of%20Teicoplanin%20for%20Children_resubmission_23072017.docx