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Nonparametric Population Analysis Of Amikacin Pharmacokinetic Data In A Pediatric Population.

Merle Y.(1), Treluyer JM* (2), Tonnelier S (2), Rey E (2), Pons G (2).

(1) INSERM U436, CHU Pitie-Salpetriere, Paris, France. (2) Pharmacologie Perinatale et Pediatrique, Universite Rene-Descartes, Hopital Saint Vincent de Paul, Paris, France.

The aims of our work were: i) to describe amikacin pharmacokinetics in populations of neonates, infants and children; ii) to determine the extent to which various covariates accounted for interindividual variability; iii) to compare the performances in terms of nephrotoxicity and therapeutic efficiency of a once daily and a twice daily regimen in our population. Therapeutic drug monitoring data were retrospectively collected from 155 patients and analysed by the nonparametric maximum likelihood method (NPML), nine covariates being included in the analysis. We investigated the extent to which each covariate accounted for the variability of each parameter by calculating the relative expected reduction of variance of the parameter distribution associated with each covariate. The relationships (if any) between parameters and covariates were explored by a graphical method. Amikacin plasma concentrations were simulated from Bayesian individual kinetic parameter estimates for the two studied dosing schedules. Our results illustrate the high interindividual variability of both clearance and distribution volume. The role of postnatal age and body weight in explaining this variability was also emphasized as well as the influence of plasma creatinine on clerarance. For both schedules the percentages of subjects with predicted minimum concentrations below 10 mg/L were close to 100%. In contrast the percentage of patients with a ratio "predicted maximum plasma concentrations/MIC" greater than 8 was higher for the once daily regimen than for the b.i.d. regimen for the considered MIC values. Since this threshold ratio is related to the treatment efficiency this result emphasizes the benefit of the once daily regimen.