Y. Merlé (1,2), J.M. Tréluyer (2,3), E. Rey (3), J. Dimet (3), G. Leleu (4), S. Blanche (5).
(1) INSERM, France, (2) EA 1833, University René Descartes, Paris, France, (3) Department of Clinical Pharmacology, CHU Cochin-Saint Vincent de Paul, Paris, France, (4) Medical department of Infectiology-Immunology, BMS France, Rueil-Malmaison, France, (5) Department of paediatric immunohaematology. CHU Necker- Enfants malades, Paris, France.
Objectives: The aims of our work were: i) to describe the reverse transcriptase inhibitor stavudine pharmacokinetics (PK) in populations of neonates, infants, children and adults; ii) to determine the extent to which various covariates account for PK interindividual variability; iii) to investigate the relationship between exposure and age and body weight.
Methods: Therapeutic drug monitoring data were retrospectively collected from 452 patients and analysed by the NPML1 method, six covariates being included in the analysis (age, body weight, sex, plasma creatinine, urea, and galenical form). We investigated the extent to which each covariate accounted for the variability of each PK parameter by computing the relative expected reduction of parameter variability due to each covariate2. The relationships (if any) between PK parameters and covariates were explored by a graphical method3. The area under the curve during 24 hours (AUC 24h) was calculated for each patient from the Bayesian individual parameters estimates. A nonparametric correlation analysis was then performed between AUC 24h and the age and weight.
Results: Our results illustrate the high interindividual variability of both apparent clearance (CL/F) and volume of distribution (V/F) (104 % and 42 % respectively). Age and weight were significant covariates for CL/F variability and age was a significant covariate for variability of V/F. Plasma creatinine was a significant covariate for variability of elimination constant rate and in patients with renal impairment. Despite the moderate increase in estimated AUC 24h, significant correlations were found between exposure and age or weight (p < 10-3).
Conclusion: Age, weight, and plasma creatinine were identified as covariates that explain variability in the pharmacokinetic parameters of stavudine in a heterogeneous population (neonates to elderlies). Stavudine exposure was related to age and weight.
References:
[1] Mallet A. A maximum likelihood estimation method for random coefficient regression models. Biometrika 1986; 73: 645-656.
[2] Tréluyer JM, Merlé Y, Semlali A, Pons G. Population pharmacokinetic analysis of netilmicin in neonates and infants with use of a nonparametric method. Clin Pharmacol Ther 2000; 67 (6): 600-9.
[3] Mentré F, Pousset F, Comets E, Plaud B, Diquet B, Montalescot G, et al. Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients. Clin Pharmacol Ther 1998; 63 (1): 64-78.
Reference: PAGE 12 () Abstr 408 [www.page-meeting.org/?abstract=408]
Poster: poster