Population Pharmacokinetics and Relationship Between Demographic and Clinical Variables and Pharmacokinetics of Gentamicin in Neonates

Abstract

Summary: Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. K el increases and V/W decreases with increasing gestational age. Almost identical results were obtained with iterative twostage Bayesian fitting (MW\PHARM 3.30) as with a non-parametric maximization algorithm (NPEM2). The effect of various covariates on drug disposition was investigated retrospectively using multiple regression analysis. Predictive power for K el increases with rising gestational age. For neonates Յ28.5 weeks and neonates >28.5 weeks and Յ30.9 weeks, the predictive power of the regression equation for K el was relatively low (r 2 respectively 0.270 and 0.364). Better predictivity was found for K el at gestational ages >30.9 weeks (r 2 ‫ס‬ 0.482), with gestational age, postnatal age, and Apgar score at 5 minutes being predictors. A very strong correlation existed between volume of distribution and weight (r 2 ‫ס‬ 0.83). Volume as a function of weight could be described with low predictivity by gestational age and to a lesser degree by Apgar score at 5 minutes (r 2 ‫ס‬ 0 .298)The developed models need appropriate prospective clinical validation.

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

“…(34) did find more individuals with an impaired GFR (Ͻ90 ml/min per 1.73 m 2 ) in the IUGR group. We found a positive correlation between amikacin clearance and GA, as has been described for aminoglycosides (18,20,(35)(36)(37)(38)(39). The absolute value of amikacin clearance (0.61 ml/kg per min) is comparable to previously reported values (0.52 to 0.6 ml/kg per min (17)(18)(19)40).…”

Clinical pharmacokinetics in optimal gentamicin dosing regimen in neonates

“…The calculated values of the pharmacokinetic parameters (CL, Vd, t 1/2 ) for each of the patients were assessed, and they are comparable with the results of previous studies [7,[17][18][19]. Statistical difference in pharmacokinetic parameters was not detected between groups, confirming linear pharmacokinetics of gentamicin.…”

Two nomograms for determining extended-dosing intervals for gentamicin in neonates

“…18 A fixed dose of 4 mg/kg was then chosen based on the analysis of current dosing protocols. [1][2][3][4][5][6] Individual elimination-rate constants (k) were determined for dosing intervals of 24, 36, and 48 hours that would produce steady-state trough gentamicin concentrations of 0.5 or 1 mg/L at 0.5 hour before the next dose. The following steady-state equation (equation 1) was used to determine these k values by iteration using Excel (Microsoft Corporation, Redmond, WA):…”

“…[1][2][3][4][5][6][7][8] The standard approach used to adjust doses and dosing intervals involves collecting both serum or plasma peak and trough concentrations of an aminoglycoside. This approach, while reasonably accurate, relies on the collection of two concentrations that coincide closely with the administration of one or two doses and therefore can lead to errors because of the need for additional blood collections and often short windows of time in which to collect these samples.…”